DK160499B - Fremgangsmaade til fremstilling af mefloquin og mellemprodukt til anvendelse herved - Google Patents
Fremgangsmaade til fremstilling af mefloquin og mellemprodukt til anvendelse herved Download PDFInfo
- Publication number
- DK160499B DK160499B DK362083A DK362083A DK160499B DK 160499 B DK160499 B DK 160499B DK 362083 A DK362083 A DK 362083A DK 362083 A DK362083 A DK 362083A DK 160499 B DK160499 B DK 160499B
- Authority
- DK
- Denmark
- Prior art keywords
- bis
- trifluoromethyl
- quinolyl
- phthalimide
- trans
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 14
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 title claims abstract description 11
- 229960001962 mefloquine Drugs 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- -1 trans-N- (6- [2,8-bis (trifluoromethyl) -4-quinolyl] -5-hexenyl) phthalamide Chemical compound 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 5
- UUOYBOUCEMVEHA-FPYGCLRLSA-N 2-[(e)-6-[2,8-bis(trifluoromethyl)quinolin-4-yl]hex-5-enyl]isoindole-1,3-dione Chemical group C1=CC=C(C(F)(F)F)C2=NC(C(F)(F)F)=CC(\C=C\CCCCN3C(C4=CC=CC=C4C3=O)=O)=C21 UUOYBOUCEMVEHA-FPYGCLRLSA-N 0.000 claims description 4
- ZOBDNOKIPPJYFU-UHFFFAOYSA-N 2-[4-[3-[2,8-bis(trifluoromethyl)quinolin-4-yl]oxiran-2-yl]butyl]isoindole-1,3-dione Chemical compound C1=CC=C(C(F)(F)F)C2=NC(C(F)(F)F)=CC(C3C(O3)CCCCN3C(C4=CC=CC=C4C3=O)=O)=C21 ZOBDNOKIPPJYFU-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000006735 epoxidation reaction Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 7
- IORZJOJSTUVEQE-UHFFFAOYSA-N 2-hex-5-enylisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCC=C)C(=O)C2=C1 IORZJOJSTUVEQE-UHFFFAOYSA-N 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 3
- RIMXEJYJXDBLIE-UHFFFAOYSA-N 6-bromohex-1-ene Chemical compound BrCCCCC=C RIMXEJYJXDBLIE-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910052740 iodine Chemical group 0.000 description 2
- 239000011630 iodine Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 229910052700 potassium Chemical group 0.000 description 2
- 239000011591 potassium Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- GIZSHQYTTBQKOQ-UHFFFAOYSA-N threo-Syringoylglycerol Chemical compound COC1=CC(C(O)C(O)CO)=CC(OC)=C1O GIZSHQYTTBQKOQ-UHFFFAOYSA-N 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- YZSRICFIQLVSMQ-UHFFFAOYSA-N 2-(trifluoromethyl)quinoline Chemical compound C1=CC=CC2=NC(C(F)(F)F)=CC=C21 YZSRICFIQLVSMQ-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- DXALAFAFIXJDOS-UHFFFAOYSA-N 4-bromo-2,8-bis(trifluoromethyl)quinoline Chemical compound C1=CC=C(C(F)(F)F)C2=NC(C(F)(F)F)=CC(Br)=C21 DXALAFAFIXJDOS-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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
- WESWYMRNZNDGBX-YLCXCWDSSA-N Mefloquine hydrochloride Chemical compound Cl.C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 WESWYMRNZNDGBX-YLCXCWDSSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- GZTUXOWPGYDWNO-UHFFFAOYSA-N [2,8-bis(trifluoromethyl)quinolin-4-yl]-pyridin-2-ylmethanone Chemical compound C=12C=CC=C(C(F)(F)F)C2=NC(C(F)(F)F)=CC=1C(=O)C1=CC=CC=N1 GZTUXOWPGYDWNO-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- IKWQWOFXRCUIFT-UHFFFAOYSA-N benzene-1,2-dicarbohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C(=O)NN IKWQWOFXRCUIFT-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- DEGPIRUPAKWDBU-UHFFFAOYSA-N isoindole-1,3-dione;sodium Chemical compound [Na].C1=CC=C2C(=O)NC(=O)C2=C1 DEGPIRUPAKWDBU-UHFFFAOYSA-N 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 229960005329 mefloquine hydrochloride Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DK 160499 B
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af mefloquin og fysiologisk tolerable syreadditionssalte deraf samt et hidtil ukendt 4-quinolinderivat, nemlig trans-N-[6-(2,8-bis(trifluormethyl)-4-quinolyl)-5-hexenyl]phthalimid, til an-5 vendelse som mellemprodukt ved denne fremgangsmåde.
Mefloquin, d,l-erythro-α-(2-piperidyl)-2,8-bis(trifluormethyl)-4-qui-nolinmethanol, er en kendt forbindelse og et værdifuldt aktivstof til bekæmpelse af malaria [jfr. fx Antimicrobial Agents Chemother. 9, 384 (1976)]. Ifølge de hidtil kendte fremgangsmåder blev mefloquin frem-10 stillet enten via metalorganiske mellemtrin [jfr. J. Med. Chem. 14, 926 (1971); tysk offentliggørelsesskrift nr. 28 06 909 og 29 40 443] eller på det sidste uden sådanne mellemprodukter ved fremgangsmåder, hvis sidste trin består i en katalytisk hydrogenering af 2-pyridyl-2,8-bis(trifluormethyl)-4-quinolylketon eller 2-pyridyl-2,8-bis(tri-15 fluormethyl)-4-quinolinacetoxymethan [jfr. europæisk patentansøgning nr. 49 776]. Ved disse fremgangsmåder forekommer der foruden erythro-formen også altid en lille mængde (ca. 5-15%) af den uønskede threo-form af 2-piperidyl-4-quinolinmethanolet, eftersom katalytisk hydrogenering aldrig forløber 100% stereoselektivt. Adskillelsen af disse 20 blandinger og renfremstillingen af erythroformen er kun mulig ved relativt omstændelige fremgangsmåder, som omfatter gentagen omkrystallisation af acetone/alkohol-blandinger, vask med acetone og krystallisation af acetonitril.
Den foreliggende opfindelse havde som formål at udvikle en syntese 25 med det lavest mulige antal trin til dannelse af mefloquin med højt totaludbytte, ved hvilken der på den ene side undgås anvendelse af metalorganiske mellemtrin og på den anden side i sidste trin dannes mefloquin med høj stereospecificitet og højst mulig renhed, nemlig udelukkende i erythroformen, således at det ikke er nødvendigt at 30 adskille threoformen fra erythroformen af a-(2-piperidyl)-2,8-bis-(trifluormethyl)-4-quinolinmethanolet.
Denne opgave er løst ifølge opfindelsen ved realisering af den i nedenstående skema illustrerede reaktionssekvens, som forløber via de to hidtil ukendte mellemprodukter trans-N-(6-[2,8-bis(trifluormeth-35 yl)-4-quinolyl]-5-hexenyl)phthalimid og trans-N-[4-(3-[2,8-bis(tri-
DK 160499 B
2 fluormethyl)-4-quinolyl] -2-oxirany 1)butyl]phthalimid. I nedenstående reaktionsskema betegner M natrium eller kalium, og X betegner chlor, brom eller iod.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at 5 a) trans-N-(6-[2,8-bis(trifluormethyl)-4-quinolyl]-5-hexenyl)phthal-imid epoxideres i et inert opløsningsmiddel til fremstilling af trans-N-[4-(3-[2,8-bis(trifluormethyl)-4-quinolyl]-2-oxirany1)butyl]-phthalimid, b) det vundne trans-N-[4-(3-[2,8-bis(trifluormethyl)-4-quinolyl]-2- 10 oxiranyl)butyl]phthalimid omsættes med hydrazinhydrat, og c) reaktionsproduktet om ønsket omdannes til et fysiologisk tolerabelt syreadditionssalt.
6-Phthalimido-l-hexen, udgangsmaterialet til nedenstående reaktions-sekvens, fremstilles ved, at man på i og for sig kendt måde omsætter 15 en 6-halogen-1-hexen (halogen = chlor, brom eller iod), fortrinsvis 6-brom-l-hexen, med phthalimid-natrium eller -kalium. Omsætningen udføres hensigtsmæssigt i nærværelse af en base, fortrinsvis i et basisk opløsningsmiddel, fx N,N-dimethylacetamid.
6-Phthalimido-i-hexenet omsættes derefter med en 4-halogen-2,8-bis-20 (trifluormethyl)quinolin (halogen = chlor, brom eller iod) til dannelse af trans-N-(6-[2,8-bis(trifluormethyl)-4-quinolyl]-5-hexenyl)-phthalimid, der anvendes som mellemprodukt ved fremgangsmåden ifølge opfindelsen og udgør et aspekt af opfindelsen. Denne reaktion foretages hensigtsmæssigt i et inert organisk opløsningsmiddel, fx ben-25 zen, toluen, acetonitril, hexamethylphosphortriamid, dimethylsul-foxid, l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinon eller 1,3-dimethyl-2-imidazolidinon, i nærværelse af en base, fx en tert.alkyl-amin såsom triethyl- eller tributylamin, samt i nærværelse af et palladiumsalt, fx palladiumdichlorid eller -diacetat, og en phosphin, 30 fx triphenylphosphin eller tri-o-tolylphosphin. Ved denne omsætning dannes udelukkende trans-produktet.
DK 160499 B
3
Det vundne trans-N- (6- [2,8-bis (trif luorme thyl) -4-quinolyl] -5-hexen-yDphthalimid epoxideres i et inert opløsningsmiddel til trans-N-[4-(3 - [ 2,8 -bis (trif luorme thyl) - 4-quinolyl J - 2 -oxiranyl)butyl J phthalimid. Epoxideringen kan foretages på i og for sig kendt måde med sædvanlige 5 oxidationsmidler såsom hydrogenperoxid (i eddikesur eller alkalisk opløsning), pereddikesyre, perbenzoesyre, m-chlorperbenzoesyre eller tert.butylhydroperoxid i nærværelse af en basisk katalysator (fx Triton® B), i et inert opløsningsmiddel, fx dichlormethan, 1,2-di-chlorethan, chloroform eller tetrahydrofuran.
DK 160499B
4
Reaktionsskema
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Mefloquin
DK 160499 B
5
Omdannelsen af trans-N- [4- (3- [2,8-bis(trifluormethyl) -4-quinolyl] -2-oxiranyl)butyl]phthalimid til mefloquin ved behandling med hydrazinhydrat foretages i et inert opløsningsmiddel, fortrinsvis i en lavere alkanol, især methanol eller ethanol, ved en temperatur, der ligger 5 mellem stuetemperatur og tilbagesvalingstemperatur, fortrinsvis under opvarmning til tilbagesvaling. Hvis der arbejdes i nærværelse af en fysiologisk tolerabel syre, fås mefloquinet i form af det ønskede syreadditionssalt. Hydrochloridet er det særlig foretrukne syreadditionssalt. Oparbejdningen foretages hensigtsmæssigt ved at skille 10 phthalylhydrazidet fra den afkølede reaktionsblanding, inddampe filtratet og behandle remanensen med en alkohol, fx methanol, ethanol eller isopropanol, fortrinsvis med methanol, eventuelt i nærværelse af 50-80 volumenprocent vand. Behandlingen kan foretages ved stuetemperatur eller, for at forøge udbyttet, under afkøling til en tempera-15 tur på noget over 0°G, hensigtsmæssigt i 6-12 timer. Mefloquin-hydro-chloridet fås på denne måde i ren form og i et næsten kvantitativt udbytte.
Opfindelsen belyses nærmere ved nedenstående eksempel:
EKSEMPEL
20 Til en suspension af 39 g kaliumphthalimid i 150 ml N,N-dimethylacet-amid sattes ved 20° C under omrøring 27 ml 6-brom-l-hexen. Efter 4 timer blev reaktionsblandingen hældt ud på 300 ml isvand og ekstraheret med ether, og den organiske fase blev vasket med 10%'s NaCl-opløsning, tørret, filtreret og inddampet til tørhed. Man fik 45 g 25 (100%) 6-phthalimido-l-hexen, smeltepunkt 17-20°C.
En blanding af 64 g 4-brom-2,8-bis(trifluormethyl)quinolin, 49 g 6-phthalimido-l-hexen, 59 ml tributylamin, 4,5 g tri-o-tolylphosphin og 1,7 g palladiumdiacetat blev opvarmet til 100°C i 300 ml hexameth-ylphosphortriamid under argonatmosfære og under omrøring i 8 timer.
30 Blandingen blev hældt ud på isvand og ekstraheret med ethylacetat.
Den organiske fase blev vasket neutral med vand, tørret og inddampet til tørhed. Den krystallinske remanens blev vasket med ether. Man fik
Claims (3)
1. Fremgangsmåde til fremstilling af mefloquin og fysiologisk tolerable syreadditionssalte deraf, kendetegnet ved, at a) trans-N-(6-[2,8-bis(trifluormethyl)-4-quinolyl]-5-hexenyl)phthali-30 mid epoxideres i et inert opløsningsmiddel til fremstilling af trans-N-[4-(3-[2,8-bis(trifluoraethyl)-4-quinolyl]-2-oxiranyl)butyl]-phthalimid, DK 160499 B b) det vundne trans-N-[4-(3-[2,8-bis(trifluormethyl)-4-quinolyl]-2-oxiranyl)butyl]phthalimid omsættes med hydrazinhydrat, og c) reaktionsproduktet om ønsket omdannes til et fysiologisk tolerabelt syreadditionssalt heraf.
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at epoxidationen gennemføres med m-chlor-perbenzoesyre.
3. Forbindelse til anvendelse som mellemprodukt ved fremgangsmåden ifølge krav 1 eller 2, 10 kendetegnet ved, at den er trans-N-(6-[2,8-bis(trif luorme thyl) -4-quinolyl]-5-hexenyl)phthalimid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH539382 | 1982-09-10 | ||
| CH539382 | 1982-09-10 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK362083D0 DK362083D0 (da) | 1983-08-08 |
| DK362083A DK362083A (da) | 1984-03-11 |
| DK160499B true DK160499B (da) | 1991-03-18 |
| DK160499C DK160499C (da) | 1991-08-26 |
Family
ID=4292814
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK362083A DK160499C (da) | 1982-09-10 | 1983-08-08 | Fremgangsmaade til fremstilling af mefloquin og mellemprodukt til anvendelse herved |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4544748A (da) |
| EP (1) | EP0103259B1 (da) |
| JP (1) | JPS5967283A (da) |
| AT (1) | ATE18222T1 (da) |
| DE (1) | DE3362313D1 (da) |
| DK (1) | DK160499C (da) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2498497A (en) * | 1949-06-10 | 1950-02-21 | Sterling Drug Inc | 2[2(phthalimido)ethyl]pyridines |
| FR2381044A1 (fr) * | 1977-02-17 | 1978-09-15 | Hoffmann La Roche | Procede pour la preparation de mefloquine |
-
1983
- 1983-08-08 DK DK362083A patent/DK160499C/da not_active IP Right Cessation
- 1983-08-22 US US06/525,341 patent/US4544748A/en not_active Expired - Fee Related
- 1983-09-06 DE DE8383108778T patent/DE3362313D1/de not_active Expired
- 1983-09-06 EP EP83108778A patent/EP0103259B1/de not_active Expired
- 1983-09-06 AT AT83108778T patent/ATE18222T1/de not_active IP Right Cessation
- 1983-09-07 JP JP58163400A patent/JPS5967283A/ja active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5967283A (ja) | 1984-04-16 |
| ATE18222T1 (de) | 1986-03-15 |
| DK362083D0 (da) | 1983-08-08 |
| EP0103259B1 (de) | 1986-02-26 |
| DE3362313D1 (en) | 1986-04-03 |
| US4544748A (en) | 1985-10-01 |
| EP0103259A1 (de) | 1984-03-21 |
| DK362083A (da) | 1984-03-11 |
| DK160499C (da) | 1991-08-26 |
| JPH0427985B2 (da) | 1992-05-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AHS | Application shelved for other reasons than non-payment | ||
| PBP | Patent lapsed |