CN108676031A - Water-soluble triazole antifungal phosphinic acid compounds and its preparation method and application - Google Patents
Water-soluble triazole antifungal phosphinic acid compounds and its preparation method and application Download PDFInfo
- Publication number
- CN108676031A CN108676031A CN201810532225.XA CN201810532225A CN108676031A CN 108676031 A CN108676031 A CN 108676031A CN 201810532225 A CN201810532225 A CN 201810532225A CN 108676031 A CN108676031 A CN 108676031A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- water
- structure shown
- phosphinic acid
- 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.)
- Withdrawn
Links
- 230000000843 anti-fungal effect Effects 0.000 title claims abstract description 26
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 26
- 150000003852 triazoles Chemical class 0.000 title claims abstract description 23
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical class O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- -1 alkyl carbon Chemical compound 0.000 claims abstract description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 239000003429 antifungal agent Substances 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims abstract description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 8
- 229960004884 fluconazole Drugs 0.000 claims description 8
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 6
- 235000010894 Artemisia argyi Nutrition 0.000 claims description 5
- 244000030166 artemisia Species 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- HUADITLKOCMHSB-AVQIMAJZSA-N 2-butan-2-yl-4-[4-[4-[4-[[(2s,4r)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3O[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 HUADITLKOCMHSB-AVQIMAJZSA-N 0.000 claims description 3
- KVSBJABNUGATFM-UHFFFAOYSA-N C(C)OP(OCC)(=O)C.[O] Chemical compound C(C)OP(OCC)(=O)C.[O] KVSBJABNUGATFM-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical group 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 229950005137 saperconazole Drugs 0.000 claims description 3
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 18
- 238000000034 method Methods 0.000 abstract description 3
- 239000002585 base Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 12
- 239000001273 butane Substances 0.000 description 11
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 6
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- NYYLZXREFNYPKB-UHFFFAOYSA-N 1-[ethoxy(methyl)phosphoryl]oxyethane Chemical compound CCOP(C)(=O)OCC NYYLZXREFNYPKB-UHFFFAOYSA-N 0.000 description 5
- LPKIGDXRQSIQBA-UHFFFAOYSA-N 4-methylidenepiperidine Chemical class C=C1CCNCC1 LPKIGDXRQSIQBA-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000008399 tap water Substances 0.000 description 5
- 235000020679 tap water Nutrition 0.000 description 5
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000001294 propane Substances 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 238000000643 oven drying Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 150000003851 azoles Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical class C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- QDGRWYSGWTVXNQ-UHFFFAOYSA-N C(C=1C(C(=O)OCC)=CC=CC1)(=O)OCC.CP Chemical compound C(C=1C(C(=O)OCC)=CC=CC1)(=O)OCC.CP QDGRWYSGWTVXNQ-UHFFFAOYSA-N 0.000 description 1
- FEJKFLBVOXZNKS-UHFFFAOYSA-P CC(C=C(C[N+](C=N)=C[NH2+]CC1(C(C(F)=CC(F)=CC)=C)[O]=C1C1(C)SC=C(C(C)=CC=C(CC#C)C#N)N1)C=C1C)C(C)=C1OC(C1NCCC1)=O Chemical compound CC(C=C(C[N+](C=N)=C[NH2+]CC1(C(C(F)=CC(F)=CC)=C)[O]=C1C1(C)SC=C(C(C)=CC=C(CC#C)C#N)N1)C=C1C)C(C)=C1OC(C1NCCC1)=O FEJKFLBVOXZNKS-UHFFFAOYSA-P 0.000 description 1
- CSXCXFAPCYMXTH-HRMVBSFLSA-N CC[C@H](/C(/[C@@](C[n]1ncnc1)([C@@H](C)N(CC1)CCC1=C)O)=C\C=C\F)F Chemical compound CC[C@H](/C(/[C@@](C[n]1ncnc1)([C@@H](C)N(CC1)CCC1=C)O)=C\C=C\F)F CSXCXFAPCYMXTH-HRMVBSFLSA-N 0.000 description 1
- HAKFWHINKUNSIR-UHFFFAOYSA-N CP(O)(O)=O.[O] Chemical compound CP(O)(O)=O.[O] HAKFWHINKUNSIR-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- NFEZZTICAUWDHU-RDTXWAMCSA-N efinaconazole Chemical compound N1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)CCC(=C)CC1 NFEZZTICAUWDHU-RDTXWAMCSA-N 0.000 description 1
- 229960003937 efinaconazole Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- DDFOUSQFMYRUQK-RCDICMHDSA-N isavuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC=C(F)C=2)F)=NC=1C1=CC=C(C#N)C=C1 DDFOUSQFMYRUQK-RCDICMHDSA-N 0.000 description 1
- 229960000788 isavuconazole Drugs 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of water-soluble triazole antifungal phosphinic acid compounds, have chemical constitution shown in formula I：
Description
Technical field
The present invention relates to medical compounds technical field more particularly to a kind of water-soluble triazole antifungal phosphinic acid compounds
And its preparation method and application.
Background technology
Triazole antifungal compound is as known in the art.In known several classifications, a kind of particularly effective class
It Bao Han not tert-hydroxyl.For example, U.S. Patent No. 5648372 discloses (2R, 3R) -3- [4- (4- cyano-phenyls) thiazole -2-
Base] -2- (2,4- difluorophenyl) -1- (1H-1,2,4- triazol-1-yls)-butyl- 2- alcoholic compounds have antifungal activity.The U.S.
The compound of patent the 5648372nd is as follows：
However, the effectiveness of such compound is limited by its low aqueous solubility.For example, above-mentioned 3-triazole compounds are in pH6.8
Water in solubility be 0.0006mg/mL.This greatly hinders the exploitation of suitable parenteral dosage form.
European Patent Application No. 829478 discloses a kind of method solving the problems, such as this, wherein passing through three nitrogen in molecule
The amino acid of a connection is connect on azoles position to increase the water solubility (as follows) of azole antifungal agents：
WO97/28169 discloses the tert-hydroxyl part that phosphonate moiety can be directly connected to antifungal compound, such as has
Just like the compound of following formula：
The number of patent application CN200685015029 of Japanese Eisai R. ＆ D. Man Co., Ltd., which is disclosed, leads to the oxygen of tert-hydroxyl
It crosses methylene and is connected to phosphonate moiety, and lysine salt can be converted into, such as have the following structure the compound of formula：
The poorly water-soluble of triazole antifungal medicine greatly hinders its parenteral system known to Fluconazole, Chinese mugwort Fluconazole etc.
The exploitation of agent needs to design and optimizes the triazole antifungal medicine with good aqueous solubility, with opening for suitable parenteral formulation
Hair, adjusts the critical natures such as solubility, dissolution, the bioavilability of API.
Invention content
The purpose of the present invention is provide a kind of water-soluble triazole antifungal phosphinic acid compounds and its system regarding to the issue above
Preparation Method.
Realizing the technical solution of the purpose is：
A kind of water-soluble triazole antifungal phosphinic acid compounds, the compound have chemical constitution shown in formula I：
Wherein, the number n of alkyl carbon is equal to 1~6, and A is that the triazole type comprising secondary hydroxyl or tert-hydroxyl is anti-true in structure shown in formula I
The non-hydroxy moieties of bacterium compound.
The chemical constitution of A chemical constitution as shown in formula II in structure shown in formula I：
Wherein, R1For the phenyl replaced by one or more halogen atoms；
R2For hydrogen atom or methyl；
R3For hydrogen atom, or and R2It is methylene together；
R4For 5 yuan or 6 member heterocyclic ring containing nitrogens, halogen ,=O, CH=CH- (C are optionally selected from by one or more6H4)-
OCH2CF2CHF2Replaced, or CN and OCH is selected from by one or more2CF2CHF2Group substitution phenyl replaced, or by
The group of group substituted-phenyl of the one or more selected from halogen and methylpyrazole base is replaced.
R in formula II1For 2,4- difluorophenyls or 2,5- difluorophenyls.
R in formula II4For triazolyl, pyrimidine radicals or thiazolyl.
The chemical constitution of A is any one of following structural formula in structure shown in formula I：
The preparation method of water-soluble triazole antifungal phosphinic acid compounds above-mentioned, includes the following steps：
(a) by the change of the compound of structure shown in compound AOH and formula IV structure shown in production III under alkaline condition
Close object：
Wherein, the group A in compound AOH is identical as the group A in claims 1 or 2；
R in formula IV and formula III5For the alkyl of hydrogen, alkyl, aryl or group substitution, R6For hydrogen, alkyl, aryl or group
The number n of substituted aryl, alkyl carbon is equal to 1~6；R in formula IV7For the ester protecting group of hydroxyl；
(b) the compound hydrolysis of phosphonate of structure shown in formula III that step (a) obtains is obtained into target compound.
In the above-mentioned technical solutions, R in formula IV7For p-toluenesulfonyl Ts or mesyl Ms.
In the above-mentioned technical solutions, the compound of structure shown in formula IV is tolysulfonyl oxygen methylphosphonic acid diethylester, step
Suddenly extraction, washing, drying, obtain mesh after the completion of the compound of structure shown in (b) Chinese style III is reacted in organic solvent with TMSBr
Mark compound.
In the above-mentioned technical solutions, the compound AOH is Fluconazole or Chinese mugwort Fluconazole or Chinese mugwort Saperconazole.
The present invention also provides water-soluble triazole antifungal phosphinic acid compounds above-mentioned in preparing antifungal drug
Using.
The beneficial effects of the invention are as follows：The antifungal triazole phosphinic acid compounds being prepared using the method for the present invention are water-soluble
Property is good, and the poorly water-soluble for solving existing triazole antifungal medicine greatly hinders the exploitation of its parenteral preparation and asks
Topic, its pharmaceutical salts or its pharmaceutically acceptable solvate, pharmaceutical salts packet can also be obtained using the compound of the present invention
Include the alkali metal salt of phosphonyl group, such as disodium or di-potassium, amine salt, such as ethylenediamine, glycine, choline, lysine salt.This
Invention is laid a good foundation for the triazole antifungal medicine of design and optimization with good aqueous solubility.
Specific implementation mode
With reference to embodiment, the invention will be further described, but not thereby limiting the invention.
Embodiment 1
Prepare target compound：Bis- (1H-1,2,4- triazol-1-yls) propane -2- base oxygen of 2- (2,4 difluorobenzene base) -1,3-
Base) methylphosphonic acid, it operates in accordance with the following steps：
(a) bis- (1H-1,2,4- triazol-1-yls) propane -2- bases oxygroups of 2- (2,4 difluorobenzene base) -1,3- are prepared) methyl
Diethyl phosphonate：
THF is added equipped with mechanical agitator, nitrogen protection, thermometer device in the 1L three-necked flasks of oven drying thereto
(250mL) and sodium hydride (14.5g, 0.363mol, 60%).By the 2- being dissolved in 150mLTHF (2,4 difluorobenzene base) -1,3-
Bis- (1H-1,2,4- triazol-1-yls) -2- propyl alcohol (formula B compounds represented, Fluconazole) (36g, 0.118mol) are used at room temperature
In 20 minutes suspension being added drop-wise to after the stirring.After stirring 45 minutes, then it was added dropwise with 15 minutes and tolysulfonyl oxygen is added
Methylphosphonic acid diethylester (DETP) (55g, 0.171mol).Reaction mixture stirs 4 hours at about 50 DEG C makes reaction complete.
HPLC detection reactions terminate, and acetic acid 17.5g and water 30ml is added and is quenched to reaction, is then concentrated under reduced pressure, dense
Dichloromethane 200ml and tap water 80ml is added in contracting object, organic layer, organic layer is taken to washed once with saturated brine after layering.
Organic layer is with MgSO4Dry and be concentrated under reduced pressure to give the compound (46.6g, 86.5%) of structure shown in the formula D of jelly.
m/z：457(MH+)
1H NMR (500MHz, CDCl3)：δ=1.29 (t, 6H), 3.85 (s, 2H), 4.15 (s, 4H), 4.19 (q, 4H),
6.61-6.68 (m, 1H), 6.90-6.94 (m, IH), 7.30-7.40 (m, 1H), 8.06 (s, 2H), 8.77 (s, 2H).
(b) bis- (1H-1,2,4- triazol-1-yls) propane -2- bases oxygroups of 2- (2,4 difluorobenzene base) -1,3- are prepared) methyl
Phosphonic acids：
(2- (2,4 difluorobenzene the base) -1,3- of structural compounds shown in crude 46g formulas D is added in 500mL three-necked flasks
Bis- (1H-1,2,4- triazol-1-yls) propane -2- bases oxygroups) methylphosphonic acid diethylester) and acetonitrile 240mL.It is added into the solution
Bromotrimethylsilane (TMSBr) (54g, 0.35mol), is heated to 82 DEG C of return stirrings 6 hours, and HPLC detection reactions are completed, instead
Mixture is answered then to be concentrated under reduced pressure.Dichloromethane 150ml and tap water 200ml is added in concentrate, phase of fetching water after extracting and demixing
Layer, 50%NaOH is added in water layer and adjusts pH value 3~4, solid is precipitated in water phase, continues to stir 4 hours, filtration product, use is molten
Liquid acetone: water (v/v=2/1,60ml) washing, 50 DEG C are dried under vacuum, obtain the target compound of structure shown in formula V
(29.6g, 73.9%).M.p.92 DEG C~95 DEG C.
m/z：401(MH+)。
1H NMR (500MHz, CDCl3)：δ=4.17 (s, 4H), 4.25 (s, 2H), 6.62-6.70 (m, 1H), 6.90-
6.94 (m, IH), 7.30-7.40 (m, 1H), 8.08 (s, 2H), 8.80 (s, 2H).
Elemental analysis measured value：C,41.95；H,3.78；N,21.02.C14H15F2N6O4P theoretical values：C,42.01；H,
3.78；N,21.00.
Embodiment 2
Prepare target compound：(2R, 3R) -2- (2,4 difluorobenzene base) -3- (4- methylenepiperidines base -1- bases) -1-
(1H-1,2,4- triazol-1-yls) butane -2- bases oxygroup) methylphosphonic acid, it operates in accordance with the following steps：
(a) (2R, 3R) -2- (2,4 difluorobenzene base) -3- (4- methylenepiperidines base -1- bases) -1- (1H-1,2,4- are prepared
Triazol-1-yl) butane -2- bases oxygroup) methylphosphonic acid diethylester
The 500mL three-necked flasks of oven drying are added thereto equipped with mechanical agitator, nitrogen protection, thermometer device
THF (80mL) and sodium hydride (9g, 0.23mol, 60%).(2R, 3R) -2- (2,4 difluorobenzene base)-of 120mL THF will be dissolved in
3- (4- methylenepiperidines base -1- bases) -1- (1H-1,2,4- triazol-1-yls) butane -2- alcohol (compound of structure shown in formula E,
Efinaconazole, end Fluconazole) (25g, 0.072mol) suspension for being added drop-wise to after the stirring with 15 minutes at room temperature
In.After stirring 45 minutes, then it was added dropwise with 15 minutes and tolysulfonyl oxygen methylphosphonic acid diethylester (34g, 0.105mol) is added.
Reaction mixture stirs 6 hours at about 50 DEG C makes reaction complete.
HPLC detection reactions terminate, and acetic acid 11.5g and water 25ml is added and is quenched to reaction, is then concentrated under reduced pressure, dense
Dichloromethane 150ml and tap water 50ml is added in contracting object, organic layer, organic layer is taken to washed once with saturated brine after layering.
Organic layer is with MgSO4Dry and be concentrated under reduced pressure to give structure shown in the formula F of light yellow oil compound (28.2g,
78.6%).
m/z：499(MH+)
1H NMR (500MHz, CDCl3)：δ=1.12 (d, 3H), 1.30 (t, 6H), 2.06 (t, 4H), 2.46 (t, 4H),
3.49 (q, 1H), 3.85 (d, 2H), 4.04 (d, 1H), 4.22 (q, 4H), 4.36 (d, 1H), 4.92 (s, 1H), 5.11 (s, 1H),
6.61 (t, 1H), 6.90-6.93 (m, IH), 7.31-7.38 (m, 1H), 8.03 (s, 1H), 8.75 (s, 1H).
(b) (2R, 3R) -2- (2,4 difluorobenzene base) -3- (- 1 base of 4- methylenepiperidines base) -1- (1H-1,2,4- tri- are prepared
Azoles -1- bases) butane -2- bases oxygroup) methylphosphonic acid
Crude 26g (compound of structure shown in formula F, (2R, 3R) -2- (2,4- bis- are added in 500mL three-necked flasks
Fluorophenyl) -3- (4- methylenepiperidines base -1- bases) -1- (1H-1,2,4- triazol-1-yls) butane -2- bases oxygroup) methylphosphonic acid
Diethylester) and acetonitrile 140mL.TMSBr (30g, 0.20mol) is added into the solution, it is small to be heated to 82 DEG C of return stirrings 7.5
When, HPLC detection reactions are completed, and reaction mixture is then concentrated under reduced pressure.Dichloromethane 100ml and tap water are added in concentrate
160ml, aqueous layer after extracting and demixing are added 50%NaOH in water layer and adjust pH value 3~4, solid is precipitated in water phase, continues to stir
It mixes 5 hours, filtration product, with solution acetone: water (v/v=1/1,50ml) washs, and 50 DEG C are dried under vacuum, obtain formula VI
The target compound (14.8g, 64.1%) of shown structure.M.p.121 DEG C~123 DEG C.m/z：443(MH+)
1H NMR (500MHz, CDCl3)：δ=1.14 (d, 3H), 2.04 (t, 4H), 2.38 (t, 4H), 3.50 (q, 1H),
3.66 (d, 2H), 4.02 (d, 1H), 4.30 (d, 1H), 4.92 (s, 1H), 5.11 (s, 1H), 6.62 (t, 1H), 6.91-6.94
(m, IH), 7.31-7.38 (m, 1H), 8.04 (s, 1H), 8.74 (s, 1H)
Elemental analysis measured value：C,51.285；H,6.15；N,12.63.C19H27F2N4O4P theoretical values：C,51.35；H,
6.12；N,12.61.
Embodiment 3
Prepare target compound：(2R, 3R) -3- (4- (4- benzonitriles base) thiazol-2-yl) -2- (2,4- difluorophenyl) -1-
(1H-1,2,4- triazol-1-yls)-butane -2- bases oxygroup) methylphosphonic acid
(a) prepare (2R, 3R) -3- (4- (4- benzonitriles base) thiazol-2-yl) -2- (2,4- difluorophenyl) -1- (1H-1,2,
4- triazol-1-yls)-butane -2- bases oxygroup) methylphosphonic acid diethylester
The 500mL three-necked flasks of oven drying are added thereto equipped with mechanical agitator, nitrogen protection, thermometer device
THF (50mL) and sodium hydride (4.3g, 0.11mol, 60%).(2R, 3R) -3- (4- (4- benzonitriles base) of 60mL THF will be dissolved in
Thiazol-2-yl) -2- (2,4- difluorophenyl) -1- (1H-1,2,4- triazol-1-yls)-butane -2- bases oxygroup) butane -2- alcohol (formulas
The compound of structure shown in G, Isavuconazole, end Saperconazole) (15g, 0.034mol) be added drop-wise to 15 minutes at room temperature
In suspension after the stirring.After stirring 45 minutes, then it was added dropwise with 15 minutes and tolysulfonyl oxygen methylphosphonic acid diethyl is added
Ester (18g, 0.56mol).Reaction mixture stirs 6 hours at about 50 DEG C makes reaction complete.
HPLC detection reactions terminate, and acetic acid 5.5g and water 15ml is added and is quenched to reaction, is then concentrated under reduced pressure, concentrates
Dichloromethane 80ml and tap water 50ml is added in object, organic layer, organic layer is taken to washed once with saturated brine after layering.It is organic
Layer is with MgSO4Dry and be concentrated under reduced pressure to give the compound (16.4g, 82.2%) of structure shown in the formula H of light yellow oil.
m/z：588(MH+)
1H NMR (500MHz, CDCl3)：δ=1.25-1.29 (m, 9H), 3.64 (q, 1H), 3.85 (s, 2H), 4.03 (d,
IH), 4.12-4.16 (q, 4H), 4.28 (d, IH), 6.64 (m, 1H), 6.95 (m, 1H), 7.34 (m, 1H), 7.68 (s, 1H),
7.81-7.83 (d, 2H), 7.98-8.00 (d, 2H), 8.18 (s, 1H), 8.79 (s, 1H).
(b) prepare (2R, 3R) -3- (4- (4- benzonitriles base) thiazol-2-yl) -2- (2,4- difluorophenyl) -1- (1H-1,2,
4- triazol-1-yls)-butane -2- bases oxygroup) methylphosphonic acid
Compound ((2R, 3R) -3- (4- (4- cyanogen of structure shown in crude 16g formulas H is added in 250mL three-necked flasks
Phenyl) thiazol-2-yl) -2- (2,4- difluorophenyl) -1- (1H-1,2,4- triazol-1-yls)-butane -2- bases oxygroup) methylphosphine
Diethyl phthalate) and acetonitrile 100mL.TMSBr (14.6g, 0.095mol) is added into the solution, is heated to 82 DEG C of return stirrings 6
Hour, HPLC detection reactions are completed, and reaction mixture is then concentrated under reduced pressure.Dichloromethane 150ml and originally is added in concentrate
Water 200ml, aqueous layer after extracting and demixing are added 50%NaOH in water layer and adjust pH value 3~4, solid is precipitated in water phase, continues
Stirring 4 hours, filtration product, with solution acetone: water (v/v=2/1,30ml) washs, and 50 DEG C are dried under vacuum, obtain formula
The target compound (9.4g, 65%) of structure shown in VII.M.p.126 DEG C~128 DEG C.m/z：532(MH+)
1H NMR (500MHz, CDCl3)：δ=1.25 (d, 3H), 3.44 (s, 2H), 3.64 (q, 1H), 4.03 (d, IH),
4.28 (d, IH), 6.65 (m, 1H), 6.94 (m, 1H), 7.32 (m, 1H), 7.66 (s, 1H), 7.80-7.82 (d, 2H), 7.96-
7.98 (d, 2H), 8.16 (s, 1H), 8.77 (s, 1H).
Elemental analysis measured value：C,51.88；H,3.76；N,13.22.C23H20F2N5O4PS theoretical values：C,51.98；H,
3.79；N,13.18.
Embodiment 4
The water-soluble ratio of water solubility parent compound corresponding to its of the compound and its disodium salt of embodiment 1,2,3
Compared with as a result see the table below：
Claims (10)
1. a kind of water-soluble triazole antifungal phosphinic acid compounds, it is characterised in that：The compound has chemistry shown in formula I
Structure：
Wherein, the number n of alkyl carbon is equal to 1~6, and A is the antifungal triazole comprising secondary hydroxyl or tert-hydroxyl in structure shown in formula I
Close the non-hydroxy moieties of object.
2. water-soluble triazole antifungal phosphinic acid compounds as described in claim 1, it is characterised in that：The change of A in structure shown in formula I
Learn structure chemical constitution as shown in formula II：
Wherein, R1For the phenyl replaced by one or more halogen atoms；
R2For hydrogen atom or methyl；
R3For hydrogen atom, or and R2It is methylene together；
R4For 5 yuan or 6 member heterocyclic ring containing nitrogens, halogen ,=O, CH=CH- (C are optionally selected from by one or more6H4)-
OCH2CF2CHF2Replaced, or CN and OCH is selected from by one or more2CF2CHF2Group substitution phenyl replaced, or by
The group of group substituted-phenyl of the one or more selected from halogen and methylpyrazole base is replaced.
3. water-soluble triazole antifungal phosphinic acid compounds as claimed in claim 2, it is characterised in that：R in formula II1It is 2,4-
Difluorophenyl or 2,5- difluorophenyls.
4. water-soluble triazole antifungal phosphinic acid compounds as claimed in claim 2, it is characterised in that：R in formula II4For triazole
Base, pyrimidine radicals or thiazolyl.
5. water-soluble triazole antifungal phosphinic acid compounds as described in claim 1, it is characterised in that：The change of A in structure shown in formula I
It is any one of following structural formula to learn structure：
6. the preparation method of water-soluble triazole antifungal phosphinic acid compounds described in any one of claim 1 to 5, feature exist
In：Include the following steps：
(a) by the compound of the compound of structure shown in compound AOH and formula IV structure shown in production III under alkaline condition：
Wherein, the group A in compound AOH is identical as the group A in claims 1 or 2；
R in formula IV and formula III5For the alkyl of hydrogen, alkyl, aryl or group substitution, R6Replace for hydrogen, alkyl, aryl or group
Aryl, the number n of alkyl carbon is equal to 1~6；R in formula IV7For the ester protecting group of hydroxyl；
(b) the compound hydrolysis of phosphonate of structure shown in formula III that step (a) obtains is obtained into target compound.
7. the preparation method as shown in claim 6, it is characterised in that：R in formula IV7For p-toluenesulfonyl Ts or mesyl
Ms。
8. the preparation method as shown in claim 7, it is characterised in that：The compound of structure shown in formula IV is tolysulfonyl oxygen
Methylphosphonic acid diethylester, the compound of structure shown in step (b) Chinese style III extract after the completion of being reacted in organic solvent with TMSBr
It takes, wash, dry, obtain target compound.
9. the preparation method as shown in claim 8, it is characterised in that：The compound AOH is Fluconazole or Chinese mugwort Fluconazole
Or Chinese mugwort Saperconazole.
10. water-soluble triazole antifungal phosphinic acid compounds described in any one of claim 1 to 5 are in preparing antifungal drug
Application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810532225.XA CN108676031A (en) | 2018-05-29 | 2018-05-29 | Water-soluble triazole antifungal phosphinic acid compounds and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810532225.XA CN108676031A (en) | 2018-05-29 | 2018-05-29 | Water-soluble triazole antifungal phosphinic acid compounds and its preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108676031A true CN108676031A (en) | 2018-10-19 |
Family
ID=63808644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810532225.XA Withdrawn CN108676031A (en) | 2018-05-29 | 2018-05-29 | Water-soluble triazole antifungal phosphinic acid compounds and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108676031A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1200480A (en) * | 1997-04-16 | 1998-12-02 | 株式会社三丰 | Reduced offset high accuracy induced current position transducer |
| CN1210540A (en) * | 1996-02-02 | 1999-03-10 | 辉瑞研究开发公司 | Triazole derivatives useful in therapy |
| CN1309660A (en) * | 1998-07-16 | 2001-08-22 | 阿文蒂斯药物德国有限公司 | Phosphinous and phosphonic acid derivs. used as medicaments |
| CN1395485A (en) * | 2000-01-20 | 2003-02-05 | 布里斯托尔-米尔斯·斯奎布公司 | Water soluble prodrugs of azole compounds |
| CN101279953A (en) * | 2007-04-06 | 2008-10-08 | 何广卫 | Triazole derivatives used in therapy and medicine salt thereof |
| CN101824002A (en) * | 2010-05-13 | 2010-09-08 | 南京华威医药科技开发有限公司 | Water soluble triazole compound and synthesis method thereof |
| US20100331282A1 (en) * | 2009-06-24 | 2010-12-30 | Masayuki Matsukura | Pyridine derivative containing ((phosphonooxy)methyl)pyridinium ring, and antifungal agent containing these derivative |
-
2018
- 2018-05-29 CN CN201810532225.XA patent/CN108676031A/en not_active Withdrawn
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1210540A (en) * | 1996-02-02 | 1999-03-10 | 辉瑞研究开发公司 | Triazole derivatives useful in therapy |
| CN1200480A (en) * | 1997-04-16 | 1998-12-02 | 株式会社三丰 | Reduced offset high accuracy induced current position transducer |
| CN1309660A (en) * | 1998-07-16 | 2001-08-22 | 阿文蒂斯药物德国有限公司 | Phosphinous and phosphonic acid derivs. used as medicaments |
| CN1395485A (en) * | 2000-01-20 | 2003-02-05 | 布里斯托尔-米尔斯·斯奎布公司 | Water soluble prodrugs of azole compounds |
| CN101279953A (en) * | 2007-04-06 | 2008-10-08 | 何广卫 | Triazole derivatives used in therapy and medicine salt thereof |
| US20100331282A1 (en) * | 2009-06-24 | 2010-12-30 | Masayuki Matsukura | Pyridine derivative containing ((phosphonooxy)methyl)pyridinium ring, and antifungal agent containing these derivative |
| CN101824002A (en) * | 2010-05-13 | 2010-09-08 | 南京华威医药科技开发有限公司 | Water soluble triazole compound and synthesis method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5215254B2 (en) | Process for producing novel phosphorus-based biphenols and derivatives thereof | |
| CN1178665C (en) | Water soluble prodrugs of azole compounds | |
| US6235728B1 (en) | Water-soluble prodrugs of azole compounds | |
| KR20150064747A (en) | A process for the preparation of acylphosphanes | |
| PL113916B1 (en) | Process for preparing novel n-phosphonomethylglycine triesters | |
| CN101861312B (en) | 2-[4-(pyrazol-4-ylalkyl)piperazin-1-yl]-3-phenyl pyrazines and pyridines and 3-[4-(pyrazol-4-ylalkyl)piperazin-1-yl]-2-phenyl pyridines as 5-HT7 receptor antagonists | |
| CN106132947A (en) | 2 (2,4 difluorophenyl) 1,1 difluoro 1 (pyridine 2 base that 5 are substituted) 3 (1H tetrazolium 1 base) propane 2 alcohol and preparation method thereof | |
| US20230139731A1 (en) | Process for preparing mannose derivatives | |
| DK1723156T3 (en) | Process for Preparation of Pyridine Derivatives | |
| TW202140424A (en) | Gpr40 agonists | |
| CN102627778A (en) | A process for the preparation of cross-linked polyallylamines or pharmaceutically acceptable salts thereof | |
| CN108676031A (en) | Water-soluble triazole antifungal phosphinic acid compounds and its preparation method and application | |
| WO2007126042A1 (en) | 2-aminobutanol compound and use thereof for medical purposes | |
| JP3156026B2 (en) | Phosphonic acid diester derivatives | |
| Li et al. | Microwave-assisted synthesis of new 1, 2, 3-triazoles bearing an isoxazole ring by the azide-alkyne cycloaddition click chemistry | |
| FI89354C (en) | Process for the preparation of pharmacologically useful tetrahydrofurans | |
| JP2017513934A (en) | Phenanthroline phosphonic acid derivatives and their preparation and application | |
| JP3176720B2 (en) | Method for producing and purifying drug having anti-neoplastic activity, octadecyl- [2- (N-methylpiperidino) -ethyl] -phosphate, and method for preparing drug | |
| CN112480116B (en) | PKB inhibitors | |
| JP4125672B2 (en) | Intermediate halophenyl derivatives and their use in the preparation of azole derivatives | |
| CN110885323A (en) | Triazole alcohol derivative, and preparation method and application thereof | |
| CN109836458A (en) | A kind of Aldoforwe ester isomer impurities and the preparation method and application thereof | |
| CN105037428A (en) | Preparation method for coumarin-3-phosphonate derivative | |
| CA2147375C (en) | Phosphonic diester derivatives | |
| KR101195631B1 (en) | New Synthetic Method of 9-[2-phosphonomethoxyethyl]adenine |
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 | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20181019 |
|
| WW01 | Invention patent application withdrawn after publication |