CN106905165B - The synthesis and application of a kind of antimycotic drug and its intermediate - Google Patents
The synthesis and application of a kind of antimycotic drug and its intermediate Download PDFInfo
- Publication number
- CN106905165B CN106905165B CN201710152519.5A CN201710152519A CN106905165B CN 106905165 B CN106905165 B CN 106905165B CN 201710152519 A CN201710152519 A CN 201710152519A CN 106905165 B CN106905165 B CN 106905165B
- Authority
- CN
- China
- Prior art keywords
- acid
- added
- compound
- solvent
- drug
- 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.)
- Active
Links
- 230000015572 biosynthetic process Effects 0.000 title abstract description 16
- 238000003786 synthesis reaction Methods 0.000 title abstract description 15
- 239000003429 antifungal agent Substances 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims description 21
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000013461 design Methods 0.000 claims description 9
- 239000012044 organic layer Substances 0.000 claims description 9
- 238000004064 recycling Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 238000010189 synthetic method Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 229940121375 antifungal agent Drugs 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- XMWGTKZEDLCVIG-UHFFFAOYSA-N 1-(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1 XMWGTKZEDLCVIG-UHFFFAOYSA-N 0.000 claims description 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical group 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 2
- 150000002602 lanthanoids Chemical class 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- YHBDIEWMOMLKOO-UHFFFAOYSA-I pentachloroniobium Chemical compound Cl[Nb](Cl)(Cl)(Cl)Cl YHBDIEWMOMLKOO-UHFFFAOYSA-I 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 230000000843 anti-fungal effect Effects 0.000 claims 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- 239000004411 aluminium Substances 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 11
- 241000894006 Bacteria Species 0.000 abstract description 8
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 8
- 239000012453 solvate Substances 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 6
- 208000031888 Mycoses Diseases 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 5
- 241000223229 Trichophyton rubrum Species 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 230000001408 fungistatic effect Effects 0.000 abstract description 4
- 241000893976 Nannizzia gypsea Species 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 abstract description 3
- 206010059866 Drug resistance Diseases 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 206010040872 skin infection Diseases 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000009036 growth inhibition Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- DNZSDFJYAAIXIC-UHFFFAOYSA-N 1-chlorobut-2-en-1-amine Chemical compound CC=CC(N)Cl DNZSDFJYAAIXIC-UHFFFAOYSA-N 0.000 description 4
- 241001480043 Arthrodermataceae Species 0.000 description 4
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 208000002474 Tinea Diseases 0.000 description 4
- 230000037304 dermatophytes Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 4
- 229960002722 terbinafine Drugs 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010012504 Dermatophytosis Diseases 0.000 description 3
- 241001460074 Microsporum distortum Species 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000003444 phase transfer catalyst Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 230000001857 anti-mycotic effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000002543 antimycotic Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000004820 blood count Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical class OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- -1 sodium alkoxide Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- 241000222173 Candida parapsilosis Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 206010043866 Tinea capitis Diseases 0.000 description 1
- 201000010618 Tinea cruris Diseases 0.000 description 1
- 206010067197 Tinea manuum Diseases 0.000 description 1
- 241000893966 Trichophyton verrucosum Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000000629 anti-dermatophyte Effects 0.000 description 1
- 230000002160 anti-trichophyton Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229940055022 candida parapsilosis Drugs 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LMRCKXYHPYNEJV-UHFFFAOYSA-N piperazine;piperidine Chemical class C1CCNCC1.C1CNCCN1 LMRCKXYHPYNEJV-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 230000000192 social effect Effects 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 201000009862 superficial mycosis Diseases 0.000 description 1
- 208000009189 tinea favosa Diseases 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
Abstract
The invention discloses the synthesis and application of a kind of novel antimycotic drug and its intermediate.Specifically disclose (E)-1- { [3- methyl-5- (4- naphthalene methylamine-2- cyclobutenyl)-2,4,6- trihydroxy] phenyl }-1- butanone and its halogenated-2- butene-1-amine of intermediate (E)-N- (1- menaphthyl)-4- and synthesis and application.The present invention provides the compound, its salt and its applications wells containing crystalline hydrate or solvate in terms of preparation antibacterial especially antifungal drug.Antibacterial experiment in vitro shows that compound provided by the invention has fungistatic effect, especially there is good fungistatic effect to two kinds of Bacteria skin infection Trichophyton rubrums and Microsporum gypseum, there is the features such as low side effect, antimycotic drug resistance, the compound library for the treatment of superficial skin fungus infection is enriched, provides strong technical support to prepare drug or the pharmaceutical composition of anti-superficial skin fungus infection.
Description
Technical field
The present invention relates to chemistry and pharmaceutical technology field, be related to the synthesis of noval chemical compound and its synthetic method of intermediate and
Using.
Background technique
Dermatophytosis is the hair as caused by dermatophyte, skin and the mycotic infection of superficial part for referring to (toe) first, but current
Also it causes the report of deep infection.Clinically common person is favus of the scalp, ringworm of the body, jock itch, the tinea manuum, tinea pedis and dermatophytids etc..It is even
It can be involved deep tissue.Cause deep infection.Dermatophyte and its metabolite, which pass through blood circulation, can cause lesion outer skin
Allergy, claim dermatophytids.Dermatophytosis is one group of common disease and frequently-occurring disease.It goes to a doctor in case in dermatology, is inferior to skin
Scorching and eczema, and then rank first in infective factors.In China, number of patients is at least calculated with hundred million, so actively prevention and treatment
Dermatophytosis has important clinical meaning and social effect.
Clinical treatment fungal infection mainly uses antibiotic, with the extensive use of antibiotic, produces a variety of drug resistances
Mechanism makes it fight fungal drug sensitive perception and substantially reduces.So finding, safe and efficient, even different role mechanism is antimycotic
Drug is still the research and development direction of antifungal drug now.
Summary of the invention
The problem to be solved in the present invention is to fill up the type deficiency of existing active phloroglucin analog derivative, is provided a kind of new
Midbody compound, compound and drug with antibacterial activity can be prepared based on the midbody compound.
Another technical problem to be solved by the present invention is that providing a kind of new reactive compound (E) -1- { [3- methyl -5-
(4- naphthalene methylamine -2- cyclobutenyl) -2,4,6- trihydroxies] phenyl } -1- butanone, at least there is excellent antibacterial activity.
A present invention also technical problems to be solved are to provide the chloro- 2- fourth of the intermediate (E)-N- (1- menaphthyl) -4-
The preparation of alkene -1- amine and (E) -1- { [3- methyl -5- (4- naphthalene methylamine -2- cyclobutenyl) -2,4,6- trihydroxy] phenyl } -1- butanone
Method.
A present invention also technical problems to be solved are to provide the application of above compound.
The purpose of the present invention is achieved by the following technical programs:
A kind of chemical compounds I is provided, the chloro- 2- butene-1-amine of (E)-N- (1- menaphthyl)-4- is named as, there is formula (I) institute
The structural formula shown:
Preferably, X is Cl or Br.
Present invention simultaneously provides chemical compounds Is and hydrochloric acid, sulfuric acid or phosphoric acid to be formed by salt.
Contain crystalline hydrate or solvate the present invention also provides the chemical compounds I and its salt.
The chemical compounds I can be prepared by the method for synthesis, column chromatography, crystallization, extraction or preparation liquid phase preparation
It arrives.The present invention provides a kind of methods of preferred synthesis chemical compounds I, comprising the following steps:
S1. the chloro- 2- butylene amine hydrochlorate of 4- or the bromo- 2- butylene amine hydrochlorate of 4- are added in reaction flask, solvent is added
Alkali is added in dissolution；
S2., the system after step S1 to be added to alkali cools down, and stirs the lower 1 chloromethyl naphthalene that solvent dissolution is added dropwise, and stirring is anti-
It answers, recycling design, organic layer extraction is added, the washed separation organic layer of organic layer is dry, filters, recycling design is to get chemical combination
Object I.
Preferably, the mass percent of the chloro- 2- butylene amine hydrochlorate of 4- or the bromo- 2- butylene amine hydrochlorate of 4- is dense in step S1
Degree is 30%.
Preferably, solvent described in step S1 is alcohol, methylene chloride, chloroform, acetonitrile or the tetrahydrofuran of C1-C5.It is molten
The dosage of agent is appropriate.It is highly preferred that solvent is methanol or ethyl alcohol in S1.
Preferably, alkali used in step S1 is inorganic base or organic base；The further preferred potassium carbonate of the inorganic base, carbon
Sour sodium, sodium bicarbonate, sodium hydride, sodium hydroxide, Sodamide, sodium alkoxide；The further preferred triethylamine of the organic base, pyridine, piperazine
Piperidines after pyridine and the pyridine replaced or substitution.It is furthermore preferred that alkali in S1, inorganic base is potassium carbonate；Alternatively, organic base is
Triethylamine.
Preferably, the additional amount of alkali used in step S1 is according to 2~5 times of determinations of mole for accounting for reaction substrate.
Preferably, appropriate phase transfer catalyst can be added in step S2.The preferred polyethylene glycol of phase transfer catalyst
PEG-400, dosage are determined according to 10% or so of 1 chloromethyl naphthalene quality.
Preferably, the temperature of system described in step S2 is reduced to -20 DEG C~0 DEG C.It is highly preferred that the temperature of system described in step S2
Degree is reduced to -5 DEG C~0 DEG C.
Preferably, the time being stirred to react described in step S2 is 3~4 hours, preferably 3 hours.
The additional amount of 1 chloromethyl naphthalene described in step S2 according to the chloro- 2- butylene amine hydrochlorate of 4- according to 1:1~1:3's
Molar ratio is added.
Preferably, washing described in step S2 is successively with aqueous slkali and water washing.Further, the aqueous slkali is
0.1%~15% sodium hydroxide solution, 0.1%~33.2% sodium carbonate liquor or 0.1%~5% sodium bicarbonate solution.More
Preferably, the sodium hydroxide solution that the aqueous slkali is 10%.
The present invention provides the applications of the chemical compounds I, applied to as the raw material for preparing reactive compound II.Describedization
Conjunction object II is (E) -1- { [3- methyl -5- (4- naphthalene methylamine -2- cyclobutenyl) -2,4,6- trihydroxy] phenyl } -1- butanone.Compound
I and II and salt and the application for being applied to antimycotic aspect containing crystalline hydrate and solvate that they are formed.
The present invention also provides the chemical compounds I and its salt, their making containing crystalline hydrate and/or solvate of being formed
Application in terms of standby antibacterials, the application especially in terms of preparing antifungal drug, and Yu Kangzhen is shared with other drugs
In terms of bacterium.
Preferably, described to share with other drugs in antimycotic aspect, it is by the chemical compounds I and its salt and their formation
Form compound medicine containing crystalline hydrate and solvate and other drugs, in the compound medicine, the chemical compounds I and
Its salt and/or the content containing crystalline hydrate and/or solvate that they are formed are 0.1%~99.9%.
Invention also provides a kind of noval chemical compound (E) -1- [3- methyl -5- (4- naphthalene methylamine -2- cyclobutenyl) -2,4,
6- trihydroxy] phenyl } -1- butanone, with structural formula shown in formula (II):
Present invention simultaneously provides compound iis and hydrochloric acid, sulfuric acid or phosphoric acid to be formed by salt.
Contain crystalline hydrate or solvate the present invention also provides the compound ii and its salt.
The compound ii can be prepared by the method for synthesis, column chromatography, crystallization, extraction or preparation liquid phase preparation
It arrives.The present invention provides a kind of methods of preferred synthesis compound ii, comprising the following steps:
S3. 1- [(3- methyl -2,4,6- trihydroxy) phenyl] -1- butanone is weighed, solvent and lewis acid is added, under stirring
Nitrobenzene, heating reflux reaction is added；
S4. the chemical compounds I dissolved with solvent is slowly added dropwise into S3 heating reflux reaction system, continues back flow reaction, to
It is cooled to room temperature after reaction, is poured into sour water dissolves under stiring, be evaporated under reduced pressure, filter, be precipitated in filtrate pale yellow while hot
Color fine needle crystal, suction filtration obtain compound ii.
Preferably, solvent described in step S3 be the alcohol of C1~C5, methylene chloride, chloroform, acetonitrile, carbon disulfide or
Tetrahydrofuran.It is highly preferred that solvent described in step S3 is carbon disulfide, higher conversion ratio and yield can get.
Preferably, lewis acid described in step S3 is alchlor, iron chloride, boron trifluoride, columbium pentachloride or group of the lanthanides
The fluoroform sulphonate of element.It is highly preferred that lewis acid described in step S3 is alchlor.
Lewis acidic additional amount described in step S3 is rubbed according to 1- [(3- methyl -2,4,6- trihydroxy) phenyl] -1- butanone
1.1~5 times of amounts of your amount determine.The additional amount of nitrobenzene described in step S3 is according to 1- [(3- methyl -2,4,6- trihydroxy) benzene
Base] -1- butanone quality 10%~20% (mass percent) determine.
The additional amount of chemical compounds I described in step S3 is rubbed according to 1- [(3- methyl -2,4,6- trihydroxy) phenyl] -1- butanone
1~5 times of amount of your amount determines.
Preferably, the time of heating reflux reaction is 30 minutes in step S3.
Preferably, 1.5 hours of return time described in step S4.
Preferably, the concentration of sour water described in step S4 is 2N~8N；Further, the acid in the sour water can be
Organic acid or inorganic acid, further, the organic acid are the one or more of acetic acid, oxalic acid, fumaric acid or citric acid；Institute
Stating inorganic acid is the one or more of hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.It is highly preferred that acid is 4N hydrochloric acid solution in step S4.
The additional amount of sour water described in step S4 is determined according to just dissolution reactant.
Preferably, solvent described in step S4 is dehydrated alcohol.
Beneficial effects of the present invention are as follows:
The applicant's years of researches, which summarize the phloroglucin analog derivative that separation is extracted in discovery from Chinese herbal medicine, to be had very
Good anti-dermatophyte activity, but because its amount is few, and be difficult to repeated isolation and obtain, therefore the present invention carries out science to its structure
Optimization modification, provides the new reactive compound including midbody compound, is noval chemical compound, have no technology report at present
The art blank has been filled up in road.
Antibacterial is being prepared especially the present invention provides the compound, its salt and its containing crystalline hydrate or solvate
Applications well in terms of antifungal drug.Antibacterial experiment in vitro shows that compound provided by the invention has fungistatic effect, especially
It is that there is good fungistatic effect to two kinds of Bacteria skin infection Trichophyton rubrums and Microsporum gypseum, has side effect low, anti-
The features such as antifungal agent resistance, enriches the compound library for the treatment of superficial skin fungus infection, to prepare anti-superficial skin fungus infection
Drug or pharmaceutical composition provide strong technical support.
It is simple and easy invention further provides the synthetic method of the compound.
Specific embodiment
The method of the present invention is further illustrated combined with specific embodiments below.Following embodiments only for illustration, no
It can be interpreted as limitation of the present invention.Unless stated otherwise, reagent raw material used in following embodiments is regular market purchase or quotient
The raw material that industry approach obtains.
The synthesis of 1 chemical compounds I of embodiment
Synthetic route is as follows:
Synthetic reaction: in reaction flask, the 30mL ethanol solution of the chloro- 2- butylene amine hydrochlorate of 4- of 1.3g, 1.96g is added
0.1g polyethylene glycol PEG-400 is added as phase transfer catalyst in potassium carbonate, and ice bath is cooling, stirs lower dropwise addition 1g1- chloromethyl
The solution that naphthalene is dissolved with 5mL dehydrated alcohol, is stirred to react 3h.Recycling design is added 20mL methylene chloride, successively uses 10mL10%
Sodium hydroxide solution, water washing separate organic layer, and anhydrous sodium sulfate is dry, and recycling design is evaporated under reduced pressure to chemical compounds I, is
(E) the chloro- 2- butene-1-amine of-N- (1- menaphthyl)-4-.
The synthesis of 2 chemical compounds I of embodiment
Synthetic route is as follows:
Synthetic reaction: in reaction flask, the 30mL methanol solution of the chloro- 2- butylene amine hydrochlorate of 1.3g4-, 1.72g is added
Triethylamine, 0.1g polyethylene glycol PEG-400, ice bath is cooling, stirs the molten of the lower 5mL methanol dissolution that 1g1- chloromethyl naphthalene is added dropwise
Liquid is stirred to react 3.5h.20mL methylene chloride is added in recycling design, successively uses 10mL5% sodium bicarbonate solution, water washing,
Organic layer is separated, anhydrous sodium sulfate is dry, and recycling design is evaporated under reduced pressure to chemical compounds I, is that (E)-N- (1- menaphthyl) -4- is chloro-
2- butene-1-amine.
The synthesis of 3 chemical compounds I of embodiment
Synthetic route is as follows:
Synthetic reaction: in reaction flask, being added the 40mL chloroform soln of the chloro- 2- butylene amine hydrochlorate of 1.3g4-,
0.8g sodium hydroxide, 0.09g polyethylene glycol PEG-400, ice bath is cooling, stirs the lower dehydrated alcohol that 0.9g1- chloromethyl naphthalene is added dropwise
Solution is stirred to react 4h.20mL methylene chloride is added in recycling design, successively uses 10mL33.2% sodium carbonate liquor, water washing,
Organic layer is separated, anhydrous sodium sulfate is dry, and recycling design is evaporated under reduced pressure to chemical compounds I, is that (E)-N- (1- menaphthyl) -4- is chloro-
2- butene-1-amine.
The structural characterization data of any gained chemical compounds I of Examples 1 to 3 are as follows:
ESI-MS(M+H)+:246.09
1H-NMR (400MHZ, CDCl3): 7.48-7.53 (m, 3H), 7.04-7.10 (d, 2H), 7.23-7.30 (d, 2H),
5.91(dd,1H),5.85(dd,1H),4.62(s,2H),4.3(s,2H),2.3(s,1H)；
13C-NMR (100MHZ, CDCl3): δ C:135.2,134.7,134.1,130.2,130.5,128.6,128.3,
128.1,127.9,127.7,127.3,126.2,56.4,54.3,49.5；
The synthesis of 4 compound ii of embodiment
Synthetic route is as follows:
Synthetic reaction: 2.1g1- [(3- methyl -2,4,6- trihydroxy) phenyl] -1- butanone is set in a round bottom flask, is added
Enter 40mL carbon disulfide and 1.6g aluminum trichloride (anhydrous), 0.2g nitrobenzene is added under stiring, is heated to reflux half an hour, then delays
It is slow that the 3.68g chemical compounds I dissolved with 5mL carbon disulfide is added dropwise, it is cooled to room temperature after continuing reflux 1.5 hours, inclines under stiring
Enter and dissolved in 10mL4N hydrochloric acid, be evaporated under reduced pressure, filter while hot, filtrate is cooling to be precipitated light yellow fine needle crystal, being dried to obtain
Object II is closed, is (E) -1- { [3- methyl -5- (4- naphthalene methylamine -2- cyclobutenyl) -2,4,6- trihydroxies] phenyl } -1- butanone.
The synthesis of 5 compound ii of embodiment
Synthetic route is as follows:
Synthetic reaction: 2.1g1- [(3- methyl -2,4,6- trihydroxy) phenyl] -1- butanone is set in a round bottom flask, is added
Enter 30mL methanol and 1.94g iron chloride, 0.2g nitrobenzene is added under stiring, is heated to reflux half an hour, use is then slowly added dropwise
The 7.36g chemical compounds I of 5mL methanol dissolution, is cooled to room temperature after continuing reflux 1.5 hours, is poured into 15mL3N phosphoric acid under stiring
Middle dissolution, vacuum distillation, is filtered while hot, and filtrate is cooling to be precipitated light yellow fine needle crystal, is dried to obtain compound ii, is (E)-
1- { [3- methyl -5- (4- naphthalene methylamine -2- cyclobutenyl) -2,4,6- trihydroxy] phenyl } -1- butanone.
The synthesis of 6 compound ii of embodiment
Synthetic route is as follows:
Synthetic reaction: 2.1g1- [(3- methyl -2,4,6- trihydroxy) phenyl] -1- butanone is set in a round bottom flask, is added
Enter 40mL carbon disulfide and 1.84g boron trifluoride ether, 0.3g nitrobenzene is added under stiring, is heated to reflux half an hour, then
The 3.68g chemical compounds I of 5mL carbon disulfide dissolution is slowly added dropwise, is cooled to room temperature after continuing reflux 1.5 hours, inclines under stiring
Enter and dissolved in 10mL4N hydrochloric acid, be evaporated under reduced pressure, filter while hot, filtrate is cooling to be precipitated light yellow fine needle crystal, being dried to obtain
Object II is closed, is (E) -1- { [3- methyl -5- (4- naphthalene methylamine -2- cyclobutenyl) -2,4,6- trihydroxies] phenyl } -1- butanone.
The structural characterization data of 4~6 any gained chemical compounds Is of embodiment are as follows:
ESI-MS(M+H)+420.23；
1H-NMR(400MHZ,DMSO-d6):δH 7.45-7.55(m,3H),7.05-7.12(d,2H),7.23-7.31
(d,2H),6.13(dd,1H),5.91(dd,1H),5.45(S,3H),3.19-3.42(m,4H),3.10(m,2H),2.42 (S,
3H),2.4(s,1H),1.62(m,2H),1.21(S,3H)。
13C-NMR(100MHZ,CDCl3):δC 198.1,168.3,160.4,160.2,106.7,106.5,106.1,
135.1,134.8,134.2,130.3,130.1,128.5,128.3,128.2,127.7,127.5,127.4,126.2,56.4,
54.3,45.2,21.7,20.5,17.5,15.9。
The external anti-superficial mycosis effect experiment of 7 compound ii of embodiment
(1) Trichophyton rubrum (CMCC (f) T1b), Microsporum gypseum (CMCC (F) M2C), by the Chinese Academy of Medical Sciences
Institute of dermatology provides.The micro-dilution method of dermatophyte is carried out by the M38-A2 scheme that U.S. CLSI is formulated, and is described below:
SDA media surface bacterium colony is gently scraped with oese to grind mycelia using sterile grinder, and dermatophyte is suspended in sterile life
It manages in salt water, adjustment turbidity is to 0.5 Maxwell turbidity, and with blood count spore quantity and short mycelia number.Make bacterial concentration 1
×103CFU/mL to 3 × 103CFU/mL.0.5 Maxwell turbidity bacterium solution is diluted 1000 times with RPMI-1640 fluid nutrient medium,
And be subject to blood cell counting plate and count, obtain inoculation bacterium solution.With RPMI-1640 fluid nutrient medium diluted compounds I (20 μ g/mL)
Lateral doubling dilution is carried out with RPMI-1640 fluid nutrient medium in the 1st to the 10th column on 96 orifice plates, the 11st is classified as growth control
100 μ lRPMI-1640 fluid nutrient mediums are added in hole；12nd is classified as blank control, and 200 μ lRPMI-1640 Liquid Cultures are added
Then base arranges then at 1-11 and 100 μ L inoculation bacterium solution is added in each hole, at this point, the concentration of the compound ii of 1-10 column is 20 μ
G/ μ L to 0.040 μ g/ μ L, and antibacterials solution concentration (v/v) is lower than 1% in each hole, meets M27-A3 regulation.By 96 holes
Plate is placed in 35 DEG C of constant-temperature incubations 7 days, and to visually observe, depending on being equivalent to compared with growth control, to produce 85% growth inhibiting
Final concentration of MIC.
In addition, should carry out quality control in each measurement, QC plants use Candida parapsilosis (ATCC 22019), Quality Control
Drug is Terbinafine, and under the conditions of operation repetitive, QC plants of MIC so should then be considered as within the scope of 1.0~4.0 μ g/mL
Measurement result is effectively credible.Each bacterial strain calculates the geometric mean of MIC by parallel replication is operated above four times.As a result interpretation
With reference to the M38-A2 scheme of CLSI, point system is visually observed to determine fungi growing state in hole, is tested by following standard recording
As a result: (100% growth inhibition) is clarified compared to completely in each Kong Junyu growth control hole ,-；It is slightly fuzzy compared with growth control hole
(75% growth inhibition) ,+；Turbidity significantly reduces (50% growth inhibition) compared with growth control hole, ++；With growth control hole phase
Reduced turbidity slightly reduces (25% growth inhibition), +++, turbidity is suitable with growth control hole, i.e., turbidity is without reduction (no growth suppression
System) ++++.It is MIC value, experiment that this experiment, which takes the lowest concentration of drug corresponding to 85% growth inhibition compared with growth control hole,
It the results are shown in Table shown in 1 and table 2.
The interaction in vitro of the anti-Trichophyton rubrum of 1. compound ii of table studies (X ± SD) (μ g/mL)
| Test-compound | MIC range | MIC85Geometrical mean |
| Compound ii | 1.5~6.0 | 3.76±5.77 |
| Terbinafine (positive drug) | 0.5~4 | 2.17±2.98 |
The anti-Microsporum gypseum MIC of 2. compound ii of table85It is worth (μ g/mL)
| Test-compound | MIC range | MIC85Geometrical mean |
| Compound ii | 2~4 | 16.1 |
| Terbinafine (positive drug) | 0.5~10 | 10 |
The experimental results showed that from monomer MIC85Find out new compounds II to Trichophyton rubrum and gypsum sample in geometrical mean
Sporidiole bacteria has good inhibiting effect.Terbinafine within the limits prescribed, meets the requirements, as a result to the MIC of Quality-control strains
Reliably.
Claims (7)
1. a kind of Antifungal Compounds, which is characterized in that the Antifungal Compounds are (E) -1- { [3- methyl -
5- (4- naphthalene methylamine -2- cyclobutenyl) -2,4,6- trihydroxy] phenyl } -1- butanone；It is with structural formula shown in formula (II):
(II).
2. Antifungal Compounds described in claim 1 and hydrochloric acid, sulfuric acid or phosphoric acid are formed by salt.
3. the synthetic method of Antifungal Compounds described in claim 1, which comprises the following steps:
S1. alkali is added after dissolving the chloro- 2- butylene amine hydrochlorate of 4- or the bromo- 2- butylene amine hydrochlorate of 4- with solvent；
S2., the system after step S1 to be added to alkali cools down, and stirs the lower 1 chloromethyl naphthalene that solvent dissolution is added dropwise, is stirred to react, returns
Solvent is received, organic layer extraction is added, the washed separation organic layer of organic layer is dry, filters, recycling design is to get formula (I) chemical combination
Object；
(I)；
S3. 1- [(3- methyl -2,4,6- trihydroxy) phenyl] -1- butanone is weighed, solvent and lewis acid is added, is added with stirring
Nitrobenzene, heating reflux reaction；
S4. formula (I) compound dissolved with solvent is slowly added dropwise into S3 heating reflux reaction system, continues back flow reaction, to
It is cooled to room temperature after reaction, is poured into sour water dissolves under stiring, be evaporated under reduced pressure, filter, be precipitated in filtrate pale yellow while hot
Color fine needle crystal, suction filtration obtain formula (II) compound.
4. synthetic method according to claim 3, which is characterized in that solvent described in step S3 is alcohol, the dichloro of C1-C5
Methane, chloroform, acetonitrile, carbon disulfide or tetrahydrofuran；
Lewis acid described in step S3 is the fluoroform of alchlor, iron chloride, boron trifluoride, columbium pentachloride or lanthanide series
Sulfonate；
Acid in the sour water is organic acid or inorganic acid；The organic acid is one kind of acetic acid, oxalic acid, fumaric acid or citric acid
Or it is a variety of；The inorganic acid is the one or more of hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
5. the synthetic method according to claim 4, which is characterized in that solvent described in step S3 is curing
Carbon.
6. the synthetic method according to claim 4, which is characterized in that lewis acid described in step S3 is trichlorine
Change aluminium.
7. the synthetic method according to claim 4, which is characterized in that acid is 4N hydrochloric acid solution in step S4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710152519.5A CN106905165B (en) | 2017-03-14 | 2017-03-14 | The synthesis and application of a kind of antimycotic drug and its intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710152519.5A CN106905165B (en) | 2017-03-14 | 2017-03-14 | The synthesis and application of a kind of antimycotic drug and its intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106905165A CN106905165A (en) | 2017-06-30 |
| CN106905165B true CN106905165B (en) | 2019-07-26 |
Family
ID=59186465
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710152519.5A Active CN106905165B (en) | 2017-03-14 | 2017-03-14 | The synthesis and application of a kind of antimycotic drug and its intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106905165B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85109165A (en) * | 1984-11-22 | 1986-07-16 | 山道士有限公司 | Preparation technology of new high propyl alkynylamine and uses thereof |
-
2017
- 2017-03-14 CN CN201710152519.5A patent/CN106905165B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85109165A (en) * | 1984-11-22 | 1986-07-16 | 山道士有限公司 | Preparation technology of new high propyl alkynylamine and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| "Stereoselective Synthesis of Allylamines by Iron-Catalyzed Cross-Coupling of 3-Chloroprop-2-en-1-amines with Grignard Reagents. Synthesis of Naftifine";R. N. Shakhmaev，et al.;《Russian Journal of Organic Chemistry》;20041231;第50卷(第3期);322-331 |
| "Synthesis and Structure-Activity Relationships of Naftifine-Related Allylamine Antimycotics";Anton Stutz，et al.;《J. Med. Chem.》;19861231;第29卷(第1期);112-125 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106905165A (en) | 2017-06-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104003947A (en) | Sulfur/nitrogen-containing azole antifungal compound as well as preparation method and application of sulfur-containing azoles antifungal compound | |
| CN106905165B (en) | The synthesis and application of a kind of antimycotic drug and its intermediate | |
| KR20200067152A (en) | New salt and solid form of escitalopram | |
| CN111057035B (en) | Baicalein derivative and preparation method and application thereof | |
| CN104610168B (en) | Cyclohexane barbituric acid chirality spiro-compound as well as preparation method and application thereof | |
| CN111004145B (en) | Chiral optical amide substituted alpha, beta-diamino acid derivative and preparation method and application thereof | |
| CN107540680A (en) | A kind of lappaconitine acetal analog derivative and its synthetic method with antitumor activity | |
| CN103467452B (en) | A kind of benzamide compound and application thereof | |
| CN111825608A (en) | Tetrahydroquinoline and tetrahydroisoquinoline compounds and application thereof | |
| CN103012295B (en) | Optical isomerism of andiconazole as well as preparation method and application of optical isomerism | |
| CN103408541B (en) | Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof | |
| CN113292532B (en) | Polysubstituted naphthoquinone derivative and preparation method and application thereof | |
| CN113292448B (en) | Indanone imine derivative and preparation method and application thereof | |
| CN102295622A (en) | Preparation method of ranolazine | |
| CN106986821B (en) | A kind of aminomethyl pyridine analog derivative and its preparation method and application | |
| CN105461641B (en) | A kind of β lapachols list star element heterozygote and preparation method thereof and medical usage | |
| CN103040832B (en) | Application of substituted cyanobenzene in preparation of fungal infection resisting drugs | |
| CN103396414B (en) | Imidazolyl-substituted thiazocyclohexane compounds and antitumor application thereof | |
| CN107286098B (en) | compounds and their use in the treatment of colon cancer | |
| CN103382190B (en) | Thiazole-cyclohexane compound of same category and preparation method and purpose thereof | |
| CN104861026A (en) | Furan skeleton included 2H-pyrazole hydroxamic acid C21 steroid saponin aglycone derivative and preparation method and application thereof | |
| CN106083817A (en) | Pirfenidone derivant and preparation method thereof | |
| CN103435573B (en) | Benzyl-substituted thiazolocyclohexane compounds, and preparation methods and antitumor uses thereof | |
| CN104610420A (en) | Anti-tumor compound as well as preparation method and application thereof in preparation of anti-tumor drug | |
| CN103040826B (en) | Preparation and medical application of substituted pyranone compound |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200615 Address after: 510000 room 508-12, building B, No. 1, Nanxiang Second Road, Huangpu District, Guangzhou, Guangdong Province Patentee after: GUANGZHOU HAIBOTE MEDICAL TECHNOLOGY Co.,Ltd. Address before: 510006, No. 280 East Ring Road, Guangzhou University, Guangzhou, Guangdong, Panyu District Patentee before: GUANGDONG PHARMACEUTICAL University |
|
| TR01 | Transfer of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Synthesis and application of an antifungal drug and its intermediate Effective date of registration: 20220225 Granted publication date: 20190726 Pledgee: Bank of China Limited Guangzhou Yuexiu Branch Pledgor: Guangzhou Haibote Medical Technology Co.,Ltd. Registration number: Y2022980001937 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20230320 Granted publication date: 20190726 Pledgee: Bank of China Limited Guangzhou Yuexiu Branch Pledgor: Guangzhou Haibote Medical Technology Co.,Ltd. Registration number: Y2022980001937 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Synthesis and application of an antifungal drug and its intermediate Effective date of registration: 20230329 Granted publication date: 20190726 Pledgee: Bank of China Limited Guangzhou Yuexiu Branch Pledgor: Guangzhou Haibote Medical Technology Co.,Ltd. Registration number: Y2023980036866 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Granted publication date: 20190726 Pledgee: Bank of China Limited Guangzhou Yuexiu Branch Pledgor: Guangzhou Haibote Medical Technology Co.,Ltd. Registration number: Y2023980036866 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Synthesis and application of an antifungal drug and its intermediate Granted publication date: 20190726 Pledgee: Bank of China Limited Guangzhou Yuexiu Branch Pledgor: Guangzhou Haibote Medical Technology Co.,Ltd. Registration number: Y2024980010040 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |