LV12955B - Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4-ynyl)-n-methyl-1-naphthalenemethanamine (terbinafine) - Google Patents
Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4-ynyl)-n-methyl-1-naphthalenemethanamine (terbinafine) Download PDFInfo
- Publication number
- LV12955B LV12955B LVP-02-193A LV020193A LV12955B LV 12955 B LV12955 B LV 12955B LV 020193 A LV020193 A LV 020193A LV 12955 B LV12955 B LV 12955B
- Authority
- LV
- Latvia
- Prior art keywords
- methyl
- palladium
- naphthalenemethanamine
- reaction
- terbinafine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 54
- 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 title claims abstract description 38
- 229960002722 terbinafine Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 238000000746 purification Methods 0.000 claims abstract description 11
- UOORRWUZONOOLO-OWOJBTEDSA-N (E)-1,3-dichloropropene Chemical compound ClC\C=C\Cl UOORRWUZONOOLO-OWOJBTEDSA-N 0.000 claims abstract description 3
- UOORRWUZONOOLO-UHFFFAOYSA-N telone II Natural products ClCC=CCl UOORRWUZONOOLO-UHFFFAOYSA-N 0.000 claims abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 23
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 229910052763 palladium Inorganic materials 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- 235000011181 potassium carbonates Nutrition 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Natural products CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- -1 propane (E) - N - (3-Chloro-2-propenyl) - N -methyl-1-naphthalenemethanamine Chemical compound 0.000 claims description 8
- 150000003003 phosphines Chemical group 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 claims description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 5
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003426 co-catalyst Substances 0.000 claims description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- 150000002940 palladium Chemical class 0.000 claims description 5
- VRTNIWBNFSHDEB-UHFFFAOYSA-N 3,3-dichloroprop-1-ene Chemical compound ClC(Cl)C=C VRTNIWBNFSHDEB-UHFFFAOYSA-N 0.000 claims description 4
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000002941 palladium compounds Chemical class 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229960003975 potassium Drugs 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 2
- IPIOOPDWWWBYPQ-BJMVGYQFSA-N (e)-3-chloro-n-methyl-n-(naphthalen-1-ylmethyl)prop-2-en-1-amine Chemical compound C1=CC=C2C(CN(C\C=C\Cl)C)=CC=CC2=C1 IPIOOPDWWWBYPQ-BJMVGYQFSA-N 0.000 claims 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims 1
- PFIUFAQBXKLCJZ-UHFFFAOYSA-N methanamine;naphthalene Chemical compound NC.C1=CC=CC2=CC=CC=C21 PFIUFAQBXKLCJZ-UHFFFAOYSA-N 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 235000011118 potassium hydroxide Nutrition 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- 235000011121 sodium hydroxide Nutrition 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 8
- 238000002955 isolation Methods 0.000 abstract description 6
- MQRIUFVBEVFILS-UHFFFAOYSA-N n-methyl-1-naphthalen-1-ylmethanamine Chemical compound C1=CC=C2C(CNC)=CC=CC2=C1 MQRIUFVBEVFILS-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000376 reactant Substances 0.000 abstract description 6
- PPWNCLVNXGCGAF-UHFFFAOYSA-N 3,3-dimethylbut-1-yne Chemical compound CC(C)(C)C#C PPWNCLVNXGCGAF-UHFFFAOYSA-N 0.000 abstract description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YUHZIUAREWNXJT-UHFFFAOYSA-N (2-fluoropyridin-3-yl)boronic acid Chemical class OB(O)C1=CC=CN=C1F YUHZIUAREWNXJT-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 229960000699 terbinafine hydrochloride Drugs 0.000 description 3
- NMPVEAUIHMEAQP-UHFFFAOYSA-N 2-Bromoacetaldehyde Chemical compound BrCC=O NMPVEAUIHMEAQP-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical class [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 102000005782 Squalene Monooxygenase Human genes 0.000 description 2
- 108020003891 Squalene monooxygenase Proteins 0.000 description 2
- 230000001857 anti-mycotic effect Effects 0.000 description 2
- 239000002543 antimycotic Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 230000008686 ergosterol biosynthesis Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- ITSLKJVPPOREBI-GQCTYLIASA-N (e)-6,6-dimethylhept-2-en-4-ynal Chemical compound CC(C)(C)C#C\C=C\C=O ITSLKJVPPOREBI-GQCTYLIASA-N 0.000 description 1
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241001480043 Arthrodermataceae Species 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910021605 Palladium(II) bromide Inorganic materials 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- IDASTKMEQGPVRR-UHFFFAOYSA-N cyclopenta-1,3-diene;zirconium(2+) Chemical compound [Zr+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 IDASTKMEQGPVRR-UHFFFAOYSA-N 0.000 description 1
- 230000037304 dermatophytes Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BVJVHPKFDIYQOU-UHFFFAOYSA-N methyl(naphthalen-1-ylmethyl)azanium;chloride Chemical compound Cl.C1=CC=C2C(CNC)=CC=CC2=C1 BVJVHPKFDIYQOU-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical class NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Claims (4)
- LV 12955 IZGUDROJUMA FORMULA 1. (£)-A/-(6,6-dimetil-2-hepten-4-inil)-A/-metil-1 -naftalīnmetānamīna (terbinafīna) ražošanas paņēmiens no /V-metil-1 -naftalīnmetānamīna, kas ietver sekojošas stadijas: 1. stadija:/V-metil-1-naftalīn- (E)-1,3-dihlor- metānamīns propāns (£)-A/-(3-hlor-2-propenil)-/V-metil-1 -naftalīnmetānamīns 2. stadija(E)-A/-(3-hlor-2-propenil)-/V-metil-1 -naftalīnmetānamīns H3C 3,3-dimetilbuM -īns(£)-/V-(6,6-dimetil-2-hepten-4-inil)-/V-metil-1 -naftalīnmetānamīns katalizators, ko-katalizators, bāze raksturīgs ar to, ka izmantotais (£)-1,3-dihlorpropēna daudzums ir robežās no 1,0 līdz 2,0 molekvivalentiem un ka minētās reakcijas stadijas tiek veiktas secīgā kārtībā kā vienreaktora process bez starpprodukta, kas radies procesa laikā, izdalīšanas un attīrīšanas, 5 2 2 5 2 2 3. 10 4. 15 20 5. 6. 25 7. 30 35 8. izmantojot vienu šķīdinātāju sistēmu, kas ir kopēja abām reakcijas stadijām. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka abām reakcijas stadijām izmantotā šķīdinātāju sistēma ir acetons, etilmetilketons, metilizobutilketons, dimetilformamīds vai to maisījums, labāk acetons. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka izmantotais (E)-1,3-dihlorpropēna daudzums ir robežās no 1,1 līdz 1,3 molekvivalentiem. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka pirmajā stadijā izmantotā bāze ir kālija karbonāts, nātrija karbonāts, nātrija hidroksīds, kālija hidroksīds, nātrija hidrogenkarbonāts, kālija hidrogenkarbonāts, trietilamīns, piridīns, n-butilamīns, N,N-dimetilanilīns, diizopropilamīns vai šo bāzu maisījums, labāk kālija karbonāts. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka pirmajā stadijā katalizators nātrija jodīds labāk ir daudzumā no 0,01 līdz 0,2 molekvivalentiem, vislabāk daudzumā 0,1 molekvivalents. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka reakcijas gaitas pirmā stadija tiek veikta temperatūrā labāk robežās no istabas temperatūras līdz izmantotās šķīdinātāju sistēmas atteces temperatūrai, vislabāk temperatūrā no 50 līdz 80 °C. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka katalizators otrajā stadijā ir pallādija savienojums, kas satur nullvērtīgu vai divvērtīgu pallādiju, labāk pallādija kompleksus ar trešējiem fosfīniem vai pallādija sāju vai pallādija kompleksu kombinācijas, vislabāk bis(benzonitrila)pallādija hlorīds vai bis(acetonitrila)pallādija hlorīds. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka ko* katalizators reakcijas gaitas otrajā stadijā ir vara (I) halogenīds vai vara (II) halogenīds, labāk vara (I) jodīds. 3 LV 12955
- 9. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka otrajā stadijā izmantotā bāze ir piperidins, nātrija karbonāts, kālija karbonāts, nātrija hidroksīds, kālija hidroksīds, nātrija hidrogenkarbonāts, kālija 5 hidrogenkarbonāts, trietilamīns, piridīns, n-butilamīns, N,N- dimetilanilīns, pirolidīns, 1-metilpiperazīns, heksametilēnimins, 4-dimetilaminopiridīns vai šo bāzu maisījums daudzumā no 1,0 līdz 10,0 molekvivalentiem, labāk no 2,5 līdz 6,0 molekvivalentiem, vislabāk piperidins daudzumā no 2 līdz 5 molekvivalentiem. 10
- 10. Paņēmiens saskaņā ar 1. punktu, kas raksturīgs ar to, ka reakcijas gaitas otrā stadija tiek veikta labāk temperatūrā robežās no +5 °C līdz izmantotās šķīdinātāju sistēmas atteces temperatūrai, vislabāk temperatūrā no 20 līdz 30 °C. 15
- 11. Paņēmiens saskaņā ar jebkuru punktu no 1. līdz 10. punktam, kas raksturīgs ar to, ka rezultātā iegūtais (E)-/V-(6,6-dimetil-2-hepten-4-inil)-A/-metil-1-naftalīnmetānamīns tālāk tiek attīrīts papildus attīrīšanas stadijā.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SK520-2000A SK5202000A3 (en) | 2000-04-07 | 2000-04-07 | Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4- inyl)-n-methyl-1-naphthalenemethylamine (terbinaphin) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LV12955B true LV12955B (en) | 2003-04-20 |
Family
ID=20435846
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LVP-02-193A LV12955B (en) | 2000-04-07 | 2002-11-06 | Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4-ynyl)-n-methyl-1-naphthalenemethanamine (terbinafine) |
Country Status (7)
| Country | Link |
|---|---|
| AU (1) | AU2001248998A1 (lv) |
| EE (1) | EE200200583A (lv) |
| HU (1) | HUP0302919A3 (lv) |
| LT (1) | LT5051B (lv) |
| LV (1) | LV12955B (lv) |
| SK (1) | SK5202000A3 (lv) |
| WO (1) | WO2001077064A1 (lv) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100459275B1 (ko) * | 2001-12-28 | 2004-12-03 | 주식회사유한양행 | 터비나핀 또는 그의 염산염의 제조방법 |
| KR20030066186A (ko) * | 2002-02-05 | 2003-08-09 | 한솔케미언스 주식회사 | (ｅ)-터비나핀 또는 이의 염산염의 제조방법 |
| ITMI20022534A1 (it) | 2002-11-29 | 2004-05-30 | Dinamite Dipharma S P A | Procedimento per la preparazione di terbinafina mediante l'uso di platino come catalizzatore. |
| CN101389617A (zh) * | 2005-10-31 | 2009-03-18 | 詹森药业有限公司 | 制备哌嗪基和二氮杂环庚烷基苯甲酰胺衍生物的新方法 |
| CN101300242B (zh) * | 2005-10-31 | 2012-07-11 | 詹森药业有限公司 | 制备环丙基-酰胺衍生物的方法 |
| CN101624328B (zh) * | 2009-07-31 | 2011-12-14 | 山东铂源化学有限公司 | (e)-1-氯-6,6-二甲基-2-庚烯-4-炔的合成方法 |
| CN104725240B (zh) * | 2015-02-12 | 2017-05-24 | 吉林修正药业新药开发有限公司 | 一种盐酸特比萘芬z型异构体的制备方法 |
| CN105016966A (zh) * | 2015-07-31 | 2015-11-04 | 江苏恒润制药有限公司 | 一种（e）-1-氯-6,6-二甲基-2-庚烯-4-炔的制备方法 |
| CN111153807B (zh) * | 2020-01-16 | 2023-01-06 | 河南豫辰药业股份有限公司 | 一种n,n-二甲氨基氯丙烷盐酸盐的制备方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3069633D1 (en) | 1979-08-22 | 1984-12-20 | Sandoz Ag | Propenylamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals |
| CH678527A5 (en) | 1989-06-22 | 1991-09-30 | Sandoz Ag | Trans(E)-N-(1-naphthyl:methyl)-heptenyl-amine prepn. - by simultaneously converting crude mixt. contg. cis and trans isomers to salt and precipitating trans isomer |
| JP3116364B2 (ja) | 1989-10-02 | 2000-12-11 | 萬有製薬株式会社 | エンイン誘導体の製造法 |
| NZ280065A (en) | 1995-09-20 | 1998-04-27 | Apotex Inc | Preparation of n-alkyl-n-(1-naphthylmethyl)alk-2-en-4-ynylamine derivatives |
-
2000
- 2000-04-07 SK SK520-2000A patent/SK5202000A3/sk unknown
-
2001
- 2001-04-05 HU HU0302919A patent/HUP0302919A3/hu unknown
- 2001-04-05 WO PCT/SK2001/000008 patent/WO2001077064A1/en not_active Application Discontinuation
- 2001-04-05 AU AU2001248998A patent/AU2001248998A1/en not_active Abandoned
- 2001-04-05 EE EEP200200583A patent/EE200200583A/xx unknown
-
2002
- 2002-09-19 LT LT2002103A patent/LT5051B/lt not_active IP Right Cessation
- 2002-11-06 LV LVP-02-193A patent/LV12955B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2001248998A1 (en) | 2001-10-23 |
| WO2001077064A8 (en) | 2002-01-03 |
| SK5202000A3 (en) | 2001-12-03 |
| WO2001077064A1 (en) | 2001-10-18 |
| HUP0302919A2 (hu) | 2003-12-29 |
| EE200200583A (et) | 2004-04-15 |
| HUP0302919A3 (en) | 2004-09-28 |
| LT2002103A (en) | 2003-05-26 |
| LT5051B (lt) | 2003-08-25 |
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