ZA200103323B - Method of producing ketimines. - Google Patents
Method of producing ketimines. Download PDFInfo
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- ZA200103323B ZA200103323B ZA200103323A ZA200103323A ZA200103323B ZA 200103323 B ZA200103323 B ZA 200103323B ZA 200103323 A ZA200103323 A ZA 200103323A ZA 200103323 A ZA200103323 A ZA 200103323A ZA 200103323 B ZA200103323 B ZA 200103323B
- Authority
- ZA
- South Africa
- Prior art keywords
- formula
- process according
- compound
- protic solvent
- sertraline
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 74
- 150000004658 ketimines Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 61
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 53
- 238000002360 preparation method Methods 0.000 claims description 40
- 239000003054 catalyst Substances 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 31
- MGBVAZJASCWJGJ-LBPRGKRZSA-N (4s)-4-(3,4-dichlorophenyl)-n-methyl-3,4-dihydro-2h-naphthalen-1-imine Chemical compound C1([C@@H]2CCC(C3=CC=CC=C32)=NC)=CC=C(Cl)C(Cl)=C1 MGBVAZJASCWJGJ-LBPRGKRZSA-N 0.000 claims description 22
- 239000003586 protic polar solvent Substances 0.000 claims description 22
- -1 isoproponanol Substances 0.000 claims description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 13
- 238000001953 recrystallisation Methods 0.000 claims description 12
- 229960002073 sertraline Drugs 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000003456 ion exchange resin Substances 0.000 claims description 5
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 4
- 235000012211 aluminium silicate Nutrition 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 claims description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 229960002510 mandelic acid Drugs 0.000 claims description 3
- 229910000510 noble metal Inorganic materials 0.000 claims description 3
- 239000012429 reaction media Substances 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 3
- 239000010457 zeolite Substances 0.000 claims description 3
- JGMBHJNMQVKDMW-NSHDSACASA-N (4s)-4-(3,4-dichlorophenyl)-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=C(Cl)C(Cl)=CC=C1[C@H]1C2=CC=CC=C2C(=O)CC1 JGMBHJNMQVKDMW-NSHDSACASA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims 1
- 239000005995 Aluminium silicate Substances 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910021536 Zeolite Inorganic materials 0.000 claims 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims 1
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 claims 1
- JGMBHJNMQVKDMW-UHFFFAOYSA-N 4-(3,4-dichlorophenyl)-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=C(Cl)C(Cl)=CC=C1C1C2=CC=CC=C2C(=O)CC1 JGMBHJNMQVKDMW-UHFFFAOYSA-N 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 150000002466 imines Chemical class 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000011230 binding agent Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 150000004760 silicates Chemical class 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 229910052901 montmorillonite Inorganic materials 0.000 description 4
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- CHRJZRDFSQHIFI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;styrene Chemical compound C=CC1=CC=CC=C1.C=CC1=CC=CC=C1C=C CHRJZRDFSQHIFI-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- YAIQCYZCSGLAAN-UHFFFAOYSA-N [Si+4].[O-2].[Al+3] Chemical class [Si+4].[O-2].[Al+3] YAIQCYZCSGLAAN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical group C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229910052706 scandium Inorganic materials 0.000 description 1
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Description
" HL/2:21863/A
Method of producing ketimines
The present invention relates to a process for the preparation of ketimines suitable as starting materials for the preparation of pharmaceutical active ingredients such as, for example, sertraline having antidepressant properties.
The best processes hitherto for the preparation of ketimines are described, for example, in
US-A-4 536 518 or US-A-4 855 500.
In the process for the preparation of ketimines disclosed in US-A-4 536 518 (columns 9/10, } Example 1(F)), the ketone is reacted, with cooling, in an aprotic solvent, for example tetra- hydrofuran, with methylamine in the presence of titanium tetrachloride. That process has the disadvantage that it is necessary to work with tetrahydrofuran, which is readily combustible, and with titanium tetrachloride, which is not free of ecological concern. In addition, the process is expensive to perform, because the reaction is carried out with cooling. A further disadvantage of that process relates to the working-up. The product has to be precipitated with additional hexane.
In the process for the preparation of ketimines disclosed in US-A-4 855 500 (columns 5/6, claim 1), the ketone is reacted, with cooling, in an aprotic solvent, for example methylene chloride, toluene or tetrahydrofuran, with anhydrous methylamine in the presence of a molecular sieve. ? That process too has the disadvantage that it is necessary to work under anhydrous conditions with solvents that are not free of ecological concern, for example methylene chloride, or with readily combustible solvents, for example tetrahydrofuran. The molecular sieve used is expensive and has to be recycled again in an additional step. A further disadvantage of that process is that the molecular sieve has to be separated off and the product has to be precipitated with additional hexane.
There is therefore still a need to find an efficient process for the preparation of ketimines that does not have the disadvantages mentioned above and that works especially in protic solvents, for example alcohols.
The present invention accordingly relates to a process for the preparation of compounds of formula ny Chis i (tM , wherein
R,
R,
R4, R, and Rj are each independently of the others hydrogen, halogen, trifluoromethyl or
C-C,alkoxy, in which process : f (a) a compound of formula 0] 1 (2) , wherein > Ry
R,
Ry, R, and Rj are as defined for formula (1), is reacted with methylamine in a protic solvent, and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation } and/or reaction step (a) is carried out in the presence of a catalyst.
Halogen is, for example, chlorine, bromine or iodine. Chlorine is preferred.
Alkoxy having up to 4 carbon atoms is a branched or unbranched hydrocarbon radical, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. Methoxy is preferred.
According to the invention, preference is given to a process wherein (a) a compound of formula (2) is reacted with methylamine in a protic solvent and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation; or a process wherein (a) a compound of formula (2) is reacted with methylamine in a protic solvent in the presence of a catalyst to form a compound of formula (1).
Very special preference is given to a process wherein (8) a compound of formula (2) is reacted with methylamine in a protic solvent in the presence of a catalyst to form a compound of formula (1), and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation.
Of interest is a process for the preparation of compounds of formula (1) wherein
Ry is hydrogen or chlorine.
Also of interest is a process for the preparation of compounds of formula (1) wherein
R, and R, are each independently of the other hydrogen, chlorine or bromine. ; Of special interest is a process for the preparation of compounds of formula (1) wherein
Ry is hydrogen and :
R, and Rj; are chlorine. :
Particularly of special interest is a process for the preparation of compounds of formula (1) wherein the protic solvent is an a-hydric alcohol wherein a is the number 1, 2, 3 or 4
Preference is given to a process for the preparation of compounds of formula (1) wherein the protic solvent is a compound of formula (3) X(OH), wherein a is 1,2, 3or4, and when ais 1, }
X is C4-Cgalkyl, Cs-Cgeycloalkyl or -CH,CH,(OCH,CH,)uR4, b is0, 1or2, and
R, is C4-C4alkoxy, or when ais 2,
X is C,-Cgalkylene or -CH,CH,(OCH,CHy),-, wherein b is as defined above, or when ais 3,
X is C3-Cgalkanetriyl or N(CH,CHz-)3, or when a is 4,
X is C4-Cgalkanetetrayl.
Alkyl having up to 8 carbon atoms is a branched or unbranched hydrocarbon radical, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2-ethylbuty!, n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, isoheptyl, 1,1,3,3-tetramethylbuty!, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl or isooctyl.
Cs-CsCycloalkyl is, for example, cyclopentyl, cycloheptyl or especially cyclohexyl.
Alkoxy having up to 4 carbon atoms is a branched or unbranched hydrocarbon radical, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. Methoxy is preferred. ! C,-CgAlkylene is a branched or unbranched radical, for example ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene or octa- methylene.
Alkanetriyl having from 3 to 8 carbon atoms is derived from an alkane having from 3 to 8 carbon atoms wherein 3 hydrogen atoms are absent and is, for example, —CH;~CH—CH;— , —CH;CHj—CH—CH;j— , —CH;CH;—CH-—CHzCH;— OF
GH CH GH; CH= CH-CH-CH— . Glyceryl is preferred.
Alkanetetrayl having from 4 to 8 carbon atoms is derived from an alkane having from 4 to 8 y carbon atoms wherein 3 hydrogen atoms are absent and is, for example,
Te Lo —CHy—G—CHy— , CH HGH — CH , —CH;~CH;—CH—CH—CH;— Of
CH;— —CH;~CH;~CH—CH;~CH—CH-CH;— . Pentaerythrityl is preferred.
A preferred meaning of X (for a = 1) is, for example, C;-Cgalkyl, especially C4-C,alkyl, e.g. ethyl or isopropyl. :
A preferred meaning of X (for a = 2) is, for example, C,-Cgalkylene, especially C,-C alkylene, e.g. ethylene.
Of special interest is a process for the preparation of compounds of formula (1) wherein the protic solvent is a compound of formula (3) X(OH), wherein a is 1 or 2, and when ais 1,
X is C4-C,alkyl or Cs-Cgcycloalkyl, or : when a is 2,
X is C,-Calkylene.
Special preference is given to a process for the preparation of compounds of formula (1) wherein the protic solvent is methanol, ethanol, isoproponanol, n-butanol, ethylene glycol, methyl Cellosolve, cyclohexanol, diethylene glycol or triethanolamine.
Special preference is given to a process for the preparation of compounds of formula (1) wherein the protic solvent is ethanol or isopropanol.
The starting compounds of formula (2) are known or can be prepared analogously tothe . processes described in US-4 536 518.
Preferred reaction conditions for the process according to the invention (reaction step (a))
J are as follows:
The reaction can be carried out at room temperature or at elevated temperature, especially temperatures of from 20 to 100°C, e.g. from 25 to 65°C, optionally under slight pressure.
The reaction is especially carried out with a large molar excess of methylamine. Special preference is therefore given to a process for the preparation of compounds of formula (1) wherein the relative molar proportion of the compound of formula (2) to methylamineis from 1:1 to 1:100, especially from 1:1.05 to 1:50, e.g. from 1:1.5 to 1:15.
The methylamine can be used in the form of methylamine gas or in the form of a solution in an alcohol, for example ethanol.
Preferred catalysts for the process for the preparation of compounds of formula (1) are protonic acids, Lewis acids, aluminium silicates, ion exchange resins, zeolites, naturally occurring layer silicates or modified layer silicates.
Suitable protonic acids are, for example, acids of inorganic or organic salts, e.g. hydrochloric acid; sulfuric acid; phosphoric acid or sulfonic acids, for example methanesulfonic acid, p- toluenesulfonic acid or camphor-10-sulfonic acid.
A suitable Lewis acid is, for example, scandium tristriflate [Sc(OTf)s].
Suitable aluminium silicates are, for example, those widely used in the petrochemical ! industry and also known as amorphous aluminium silicates. Such compounds contain about 10-30 % silicon oxide and 70-90 % aluminium oxide.
Suitable ion exchange resins are, for example, styrene/divinyl benzene resins that also carry sulfonic acid groups, e.g. Amberlie 200° and Amberlyst® from Rohm and Haas or Dowex 50° from Dow Chemicals; perfluorinated ion exchange resins, e.g. NafionH® from DuPont; or other superacidic ion exchange resins such as those described by T. Yamaguchi, Applied
Catalysis, 81, 1-25 (1990) or M. Hino et al., J. Chem. Soc. Chem. Commun. 1980, 851-852.
Suitable zeolites are, for example, those widely used as cracking catalysts in the petro- chemical industry and known as crystalline silicon-aluminium oxides having different crystal structures. Special preference is given to the faujasites from Union Carbide, e.g. Zeolith X®
Zeolith Y® and ultrastable Zeolith Y®; Zeolith Beta® and Zeolith ZSM-12® from Mobil Oil Co.; ) and Zeolith Mordenit® from Norton.
Suitable naturally occurring layer silicates are also known as "acid earths" and are, for : example, bentonites or montmorillonites, which are mined on a large scale, ground, treated with mineral acids and calcined. Especially suitable naturally occurring layer silicates are the
Fulcat® types from Laporte Adsorbents Co., e.g. Fulcat 22A% Fulcat 22B®, Fulcat 20%, Fulcat 30% or Fulcat 40%, or the Fulmont® types from Laporte Adsorbents Co., e.g. Fulmont XMP-3® or Fulmont XMP-4%. An especially preferred catalyst for the process according to the invention is Fulcat 228%, but the other Fulcat® types and Fulmont® types are also to be included in this preferred class, because there are only very slight differences between the individual types, for example in the number of acidic centres.
Modified layer silicates are also known as "pillared clays" and are derived from the naturally occurring layer silicates described above in that they also contain, between the silicate layers, oxides of, for example, zirconium, iron, zinc, nickel, chromium, cobalt or magnesium.
That type of catalyst is widely known in the literature, as described e.g. by J. Clark et al., J.
Chem. Soc. Chem. Commun. 1989, 1353-1354, but is produced by only very few companies. Especially preferred modified layer silicates are, for example, Envirocat
EPZ-10%, Envirocat EPZG® or Envirocat EPIC® from Contract Chemicals.
Special preference is also given to a process for the preparation of compounds of formula, wherein the catalyst is a sulfonic acid, especially p-toluenesulfonic acid, methanesulfonic acid or camphor-10-sulfonic acid.
The relative molar proportion of the catalyst used to methylamine used is advantageously from 0.001:1 to 1:1, especially from 0.01:1 to 0.5:1, e.g. from 0.05:1 to 0.1:1.
The relative molar proportion of the catalyst to methylamine of 1:1 also means that the methylamine can also be used in the process according to the invention in the form of a salt, for example in the form of the methylamine hydrochloride.
Also of particular interest is a process for the preparation of compounds of formula (1) wherein the compound of formula (1) is continuously crystallised out of the reaction medium during preparation and then filtered off.
Also of special interest is a process for the preparation of compounds of formula (1) wherein the filtrate is used for a further reaction for the preparation of compounds of formula (1), the consumed amounts of compound of formula (2) and methylamine being replaced. The ) filtrate is preferably recycled from 2 to 10 times.
The present process according to the invention is accordingly also suitable as a continuous process for the preparation of the compounds of formula (1).
The water formed during the process can optionally be bound with an additional water- binder, for example molecular sieves or orthoesters, e.g. orthoformic acid trimethyl ester.
The purification step (b) is carried out in a protic solvent, especially an alcoholic solvent.
Especially preferred alcohols correspond to formula (3), especially ethanol or isopropanol.
In an especially preferred embodiment, the purification step (b) is carried out in the same solvent as reaction step (a). in a preferred process variant, the purification is carried out by recrystallisation of sertraline- imine (compound of formula (1)) under reflux. For that purpose, the isomerically pure sertraline-imine, which is usually contaminated with from 2 to 10 % sertralone and from 0.01 to 0.3 % sulfonic acid, in a suitable alcohol is introduced into a suitable reaction vessel having a stirrer and reflux condenser. The reaction mass is heated, with stirring, at reflux temperature in an inert gas atmosphere until a clear solution is obtained. The solution is cooled to the appropriate isolation temperature, the product slowly precipitating out. The suspension is filtered, the filter cake is washed with the solvent and dried. The yield of imine is from 80 to 90 %, with a sertralone content of from 0.1 to 0.3 % (HPLC), catalyst contamination of < 0.001 % and a water content of from 0.1 to 0.3 %.
In a further process variant, the recrystallisation of sertraline-imine is carried out under : pressure. For that purpose, the crude sertraline-imine and the solvent are introduced into a suitable pressurised reactor having a stirrer. The reactor is rendered inert with nitrogen and sealed. The stirrer is started and the reaction mixture is heated at the desired reaction temperature until a clear solution is obtained. The solution is cooled to the appropriate isolation temperature, the product slowly precipitating out. The suspension is filtered, the filter cake is washed with the solvent and dried.
The dissolution temperatures in the chosen alcohols are in the range of from 50 to 150°C, preferably in the range of from 70 to 140°C.
According to the boiling points of the solvents indicated, the dissolving experiments can be carried out under normal pressure or elevated pressure, but normally under reflux. } For dissolving temperatures above the boiling point, the dissolving experiments can be carried out under pressure, normally in the range of from 0 to 10 bar excess pressure, preferably in the range of from 0 to 3 bar excess pressure.
The cooling gradients are in the range of from 0.05 to 10°C/min, preferably from 0.1 to 1°C/min.
The isolation temperatures are in the range of from -20 to 40°C, preferably from 0 to 25°C.
The concentrations of crude sertraline-imine in the clear solution are in the range of from 5 to 40 % by weight, preferably from 15 to 20 % by weight.
During the process, in order to remove discolouring impurities it is possible to add adsorbents such as activated carbon or adsorber resins. They are added to the clear solution in amounts of from 1 to 10 % and are removed while hot by filtration prior to the crystallisation process.
The present invention relates also to a process for the preparation of optically pure (cis)- and/or (trans)-sertraline or enantiomerically enriched mixtures of (cis)- and (trans)-sertraline.
The process comprises the following reaction steps (I)-(l): (1) reaction of pure sertraline-ketone of formula (2) to form the sertraline-imine of formula (1) in accordance with the process of claim 1, (I) subsequent cis-selective hydrogenation using noble metal catalysts or further copper- or nickel-based catalysts to form cis-sertraline-enriched mixtures of racemic cis- and trans- sertraline, (11) subsequent racemate cleavage using mandelic acid for the selective preparation of the desired enantiomerically pure cis-isomer.
Starting from pure setraline-ketone, sertraline-imine is prepared in accordance with the process described in claim 1. In a subsequent cis-selective hydrogenation with noble metal catalysts or further copper- or nickel-based catalysts of a wide variety of supports, e.g. carbon, alo, silica, calcium carbonate, barium carbonate, barium sulfate etc., the imine is converted into cis-sertraline-enriched mixtures of racemic cis- and trans-sertraline.
In a subsequent racemate cleavage using mandelic acid, the desired enantiomerically pure cis-isomer can be crystallised selectively. ] The optically pure amine is freed with sodium hydroxide solution and converted in hydro- ! chloride form in suitable solvents into the desired polymorphous form.
The following Examples further illustrate the invention. Parts or percentages relate to weight.
Example 1: Preparation of the compound of formula (101) without catalyst and without water-binder
CHa
CO
(101) 8 cl
Cl ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 3.16 g (34.4 mmol) of a 33 % ethanolic methylamine solution and 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalinone (prepared in accordance with US-4 536 518, Example 1(E)). The round-bottomed flask is then sealed tightly with a stopper and heated at 60°C in a preheated oil bath. After about 30 minutes, a clear solution is observed for 1 to 4 minutes. The product of formula (101) then begins to crystallise. After about 40 hours, a conversion of more than 95 % has been achieved (HPLC). The reaction mixture is cooled and filtered. The residue is washed three times using 25 ml of ethanol each time and then dried in a vacuum drying cabinet at about 70°C/0.1-0.2 mbar. 4.41 g (84 %) of the compound of formula (101) are obtained.
M.p. 145-147°C.
Example 2: Preparation of the compound of formula (101) using p-toluenesuifonic acid as catalyst 20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 0.60 g (3.44 mmol) of dried p-toluenesulfonic acid (dried at 100- 110°C and 100-200 mbar), 3.16 g (34.4 mmol) of a 33 % ethanolic methylamine solution and 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalinone (prepared in accordance with US-A-4 536 518, Example 1(E)). The round-bottomed flask is then sealed : tightly with a stopper and heated at 60°C in a preheated oil bath. After about 30 minutes, a clear solution is observed for 1 to 4 minutes. The product of formula (101) then begins to crystallise. After about 3 hours, a conversion of more than 95 % has been achieved (HPLC).
The reaction mixture is cooled and filtered. The residue is washed three times using 25 mi of ethanol each time and then dried in a vacuum drying cabinet at about 70°C/0.1-0.2 mbar. 14.57 g (87 %) of the compound of formula (101) are obtained.
M.p.: 145-147°C.
Example 3: Preparation of the compound of formula (101) re-using the filtrate (recycling method) and using p-toluenesulfonic acid as catalyst ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto j in succession, with stirring, 0.6 g (3.44 mmol) of dried p-toluenesulfonic acid (dried at 100-110°C and 100-200 mbar), 12.9 g (140.2 mmol) of a 33 % ethanolic methylamine - solution and 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalinone (prepared in accordance with US-A-4 536 518, Example 1(E)). The round-bottomed flask is then sealed tightly with a stopper and heated at 30°C in a preheated oil bath. At that temp- erature at no time is a clear solution observed. After about 5 hours and 40 minutes, a conversion of more than 95 % has been achieved (HPLC). The reaction mixture is cooled "and filtered. The residue is washed once with 33 % ethanolic methylamine solution. 5.09 (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalinone [prepared in accordance with US 4 536 518, Example 1(E)] is again added to the filtrate (reaction medium) and the mixture is subjected to a further reaction cycle as described above. After 3 three further reaction cycles the residues are combined, washed three times with ethanol and then dried in a vacuum drying cabinet at about 70°C/0.1-0.2 mbar. - 22.5 g (86 %) of the compound of formula (101), m.p. 145-147°C, are obtained.
Example 4: Preparation of the compound of formula (101) using scandium tristriflate as catalyst and montmorillonite as water-binder 60 mi of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 14.2 g (155 mmol) of a 33 % ethanolic methylamine solution, 3.0 g of dried G62 montmorillonite (water-binder), 50 mg (0.3 %, 0.13 mmol) of Sc(0Tf); (scandium tristriflate) and 15.0 g (55 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)- naphthalinone (prepared in accordance with US-A-4 536 518, Example 1(E)). The round-
bottomed flask is then sealed tightly with a stopper and heated at 60°C in a preheated oil bath. After about 20 hours, a conversion of more than 95 % has been achieved (HPLC). The reaction mixture is cooled and filtered. The residue is taken up in tetrahydrofuran. The insoluble montmorillonite is filtered off and washed with tetrahydrofuran. The filtrate is concentrated using a vacuum rotary evaporator.
The residue yields 13.5 g (86 %) of the compound of formula (101).
M.p.: 145-147°C. ! Example 5: Preparation of the compound of formula (101) using scandium tristriflate as catalyst and using orthoformic acid trimethyl ester as water-binder ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 4.73 g (50 mmol) of a 33 % ethanolic methylamine solution, 2.55 g of -orthoformic acid trimethyl ester (water-binder), 100 mg (2.0 %, 0.26 mmol) of
Sc(OTf); [scandium tristriflate] and 5.0 g (17.2 mmol) of 4-(3,4-dichlorophenyl)-3,4-dihydro- 1(2H)-naphthalinone (prepared in accordance with US-A-4 536 518, Example 1(E)). The round-bottomed flask is then sealed tightly with a stopper and heated at 60°C in a preheated oil bath. After about 6 hours, a conversion of more than 95 % has been achieved (HPLC).
The reaction mixture is cooled and filtered. The residue is washed three times using 4 ml of ethanol each time and then dried in a vacuum drying cabinet at about 70°C/0.1-0.2 mbar. ; 4.5 g (86 %) of the compound of formula (101) are obtained.
M.p.: 145-147°C.
Example 6: Preparation of the compound of formula (101) without catalyst, but using ortho- formic acid trimethyl ester as water-binder 20 ml of ethanol are introduced into a 50 ml round-bottomed flask. There are added thereto in succession, with stirring, 4.73 g (50 mmol) of a 33 % ethanolic methylamine solution, 2.55 g of orthoformic acid trimethyl ester (water-binder) and 5.0 g (17.2 mmol) of 4-(3,4- dichlorophenyl)-3,4-dihydro-1(2H)-naphthalinone (prepared in accordance with
US-A-4 536 518, Example 1(E)). The round-bottomed flask is then sealed tightly with a stopper and heated at 60°C in a preheated oil bath. After about 7 hours, a conversion of more than 95 % has been achieved (HPLC). The reaction mixture is cooled and filtered. The residue is washed three times using 4 mi of ethanol each time and then dried in a vacuum drying cabinet at about 70°C/0.1-0.2 mbar. 4.5 g (86 %) of the compound of formula (101) are obtained.
M.p.: 145-147°C.
Examples 7 to 14: Preparation of sertraline-imine using various solvent/catalyst combinations i 20 g of solvent (a) are introduced into a 50 mi round-bottomed flask. 0.33 equivalent (relative to the ketone used) of catalyst (b) are added to 2.9 g of a 33 % ethanolic methylamine } solution. Heating is carried out for 4 hours at the temperature indicated. An HPLC sample is } taken, heating is carried out for a further 16 hours and the solid product of formula (101) is filtered. Finally, HPLC samples of both the product and the mother liquor are taken.
The experiment parameters and results are given in Table 1:
H .
Table 1:
Example (Temp. Solvent (a) Catalyst (b) Yield Isolated yield | rel. imine [°C] after4 h | [%) concentra- [%] contaminated] tion in the
HPLC with % mother liquor ketone [%], HPLC 30 Ethanol Methane- 46 84/3.2 sulfonic acid
Isopropanol | Methane- 29 86/8.5 sulfonic acid 11 Triethanol- | p-TsOH 92 7714.0 28 amine
J 12 Ethylene p-TsOH 93 84/3.8 <20 glycol 13 Cyclo- p-TsOH 81 64/12 18 hexanol 14 30 Ethanol Camphor- 49 80/2.9 17 sulfonic acid
Example 15: Preparation of sertraline-imine using methanesulfonic acid as catalyst
Sertralone (240.0 g; 0.825 mol) is introduced with ethanol,,s (800 ml) into a suitable reaction vessel equipped with a stirrer and gas inlet line.
The suspension is cooled to 0°C and methylamine (55.0 g; 1.762 mol) is introduced under the level, i.e. below the surface, of the solvent. Methanesulfonic acid (10 ml) is then fed in over a period of 5 minutes using a syringe.
The reaction mass is heated and stirred for 3 hours at 50°C and for 1 hour at 70°C in order to obtain conversion into the imine (> 94 %).
The reaction mixture is then cooled to 10°C, filtered and washed with cold ethanol (2 x 250 ml). The crude filter cake is dried overnight in vacuo and yields 213 g of dry
N-methyl-sertraline-imine. ; Quality and yield of the resulting imine (determined by means of HPLC): 88 % yield of sertraline.
The imine contains: 1.8 % sertralone 0.1 % water. 0.05 % methanesulfonic acid (determined using CE)
Example 16: Purification of sertraline-imine by recrystallisation from ethanol: 12 g of sertraline-imine from Example 15 are introduced into 200 ml of ethanol in a suitable reaction vessel having a stirrer, nitrogen inlet line and reflux condenser. The stirrer is started and the reaction mixture is heated at reflux temperature until a clear solution is obtained. / The solution is slowly cooled to 20°C, the product crystallising out. The suspension is filtered, the filter cake is washed with the solvent and dried. 10.6 g of sertraline-imine having the following composition (HPLC) are obtained: 88 % yield of sertraline-imine
The imine contains: 0.2 % sertralone < 0.05 % water < 0.001 % methanesulfonic acid (determined using CE).
By means of the recrystallisation it is possible both to improve product purity and to remove troublesome impurities such as water or catalyst residues.
Example 17: Preparation of sertraline-imine without catalyst (see Example 1)
Quality and yield of the imine (determined by means of HPLC): 84 % yield of sertraline-imine
The imine contains: % sertralone 0.1 % water
Example 18: Recrysallisation of sertraline-imine from catalyst-free preparation
A
The recrystallisation of imine from Example 16 is carried out with the addition of 480 mg of activated carbon. 1 hour at reflux is followed by hot (at T>70°C) clarifying filtration and subsequent cooling. The following results are obtained: 88 % yield of sertraline-imine
The imine contains: 0.2% sertralone <0.05 % water
Example 19: Recrystallisation of sertraline-imine in ethanol at temperatures above the boiling point (under pressure) g of sertraline-imine from Example 18 are introduced into 20 ml of ethanol in a suitable pressurised reaction vessel having a stirrer. The reaction mixture is heated, with stirring, at from 110°C to 115°C (pressure range from 2 to 5 bar) until a clear solution is obtained. The solution is slowly cooled to 20°C, the product precipitating out. The suspension is filtered, the filter cake is washed with the solvent and dried. 8.6 g of sertraline-imine of the following composition (HPLC) are obtained: 86 % yield of sertraline-imine
The imine contains: 0.9 % sertralone < 0.05 % water 0.001 % methanesulfonic acid (determined using CE)
Claims (26)
1. A process for the preparation of compounds of formula nC J) (1) R, R, oo wherein R4, Ry and R; are each independently of the others hydrogen, halogen, trifluoromethyl or C4-C,alkoxy, in which process (a) a compound of formula 0 S90 2) , Wherein R, R, ; R+, Ry and R; are as defined for formula (1), is reacted with methylamine in a protic solvent, and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation and/or reaction step (a) is carried out in the presence of a catalyst.
2. A process according to claim 1, wherein (a) a compound of formula (2) is reacted with methylamine in a protic solvent and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation.
3. A process according to claim 1, wherein (a) a compound of formula (2) is reacted with methylamine in a protic solvent in the presence of a catalyst to form a compound of formula (1).
4. A process according to claim 1, wherein
(a) a compound of formula (2) is reacted with methylamine in a protic solvent in the presence of a catalyst to form a compound of formula (1), and (b) the resulting compound of formula (1) is subjected to purification by recrystallisation.
5. A process according to any one of claims 1 to 4, wherein Ry; is hydrogen or chlorine.
6. A process according to any one of claims 1 to 5, wherein R, and R, are each independently of the other hydrogen, chlorine or bromine.
7. A process according to any one of claims 1 to 6, wherein } Ry is hydrogen and R; and Rj are chlorine.
8. A process according to any one of claims 1 to 7, wherein the protic solvent is an a-hydric alcohol wherein a is the number 1, 2, 3 or 4.
9. A process according to claim 8, wherein the protic solvent is a compound of formula (3) X(OH)a wherein a is1,2,3o0r4, and when ais 1, X is C4-Cgalkyl, C5s-Cgcycloalkyl or -CH,CH,(OCH,CHa)yR,, ; b is 0, 1or2, and R, is C4-C,alkoxy, or when ais 2, X is C,-Cgalkylene or -CH,CH,(OCH,CH,),-, wherein b is as defined above, or when ais 3, X is C5-Cgalkanetriyl or N(CH,CHap-)3, or when ais 4, X is C4-Cgalkanetetrayl.
' EJ N »
10. A process according to claim 9, wherein the protic solvent is methanol, ethanol, isoproponanol, n-butanol, ethylene glycol, methyl Cellosolve, cyclohexanol, diethylene glycol or triethanolamine.
11. A process according to claim 10, wherein the protic solvent is ethanol or isopropanol.
12. A process according to claim 1 or any one of claims 3 to 11, wherein the catalyst is a protonic acid, a Lewis acid, an aluminium silicate, an ion exchange resin, a zeolite, a naturally occurring layer silicate or a modified layer silicate.
13. A process according to claim 12, wherein the catalyst is a sulfonic acid. i
14. A process according to claim 13, wherein the catalyst is p-toluenesulfonic acid, methanesulfonic acid or camphor-10-sulfonic acid.
15. A process according to any one of claims 1 to 14, wherein the compound of formula (1) is continuously crystallised out of the reaction medium during preparation and then filtered off.
16. A process according to claim 15, wherein the filtrate is used for a further reaction for the preparation of the compound of formula (1). .
17. A process according to any one of claims 1 to 16, wherein the relative molar proportion of the compound of formula (2) to methylamine is from 1:1 to 1:100.
18. A process according to claim 1, 2 or any one of claims 4 to 17, wherein the purification 3 step (b) is carried out in a protic solvent.
19. A process according to claim 18, wherein the protic solvent is a compound of formula (3).
20. A process according to claim 19, wherein the protic solvent is ethanol or isopropanol.
21. A process according to claim 1, 2 or any one of claims 4 to 20, wherein purification step (b) is carried out in the same solvent as reaction step (a).
22. A process according to claim 1, 2 or any one of claims 4 to 21 21, wherein purification step (b) is carried out under reflux.
23. A process according to claim 1, 2 or any one of claims 4 to 21, wherein purification step (b) is carried out under elevated pressure.
AE IE
24. A process according to claim 1, 2 or any one of claims 4 to 23, wherein purification step (b) is carried out at a temperature of from 50 to 150°C.
25. A process according to any one of claims 1 to 24, wherein the compound of formula (1) is isomerically pure and prior to purification step (b) is contaminated with from 2to 10 % compound of formula (2) and from 0.01 to 0.3 % sulfonic acid.
26. A process for the preparation of optically pure (cis)- and/or (trans)-sertraline or enantiomerically enriched mixtures of (cis)- and (trans)-sertraline, which process comprises the following reaction steps (I)-(l11): (I) reaction of pure sertraline-ketone of formula (2) to form the sertraline-imine of formula (1) in accordance with the process of claim 1, - (Il) subsequent cis-selective hydrogenation using noble metal catalysts or further copper- or nickel-based catalysts to form cis-sertraline-enriched mixtures of racemic cis- and trans- sertraline, and (Ill) subsequent racemate cleavage using mandelic acid for the selective preparation of the desired enantiomerically pure cis-isomer.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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CH220198 | 1998-10-30 |
Publications (1)
Publication Number | Publication Date |
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ZA200103323B true ZA200103323B (en) | 2001-11-28 |
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Application Number | Title | Priority Date | Filing Date |
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ZA200103323A ZA200103323B (en) | 1998-10-30 | 2001-04-24 | Method of producing ketimines. |
Country Status (16)
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EP (1) | EP1124792B1 (en) |
JP (1) | JP2002528528A (en) |
CN (1) | CN1325381A (en) |
AR (1) | AR021005A1 (en) |
AT (1) | ATE272611T1 (en) |
AU (1) | AU767324B2 (en) |
CA (1) | CA2346900A1 (en) |
DE (1) | DE59910149D1 (en) |
ES (1) | ES2226501T3 (en) |
HU (1) | HUP0104323A3 (en) |
IL (1) | IL142367A0 (en) |
PT (1) | PT1124792E (en) |
TR (1) | TR200100942T2 (en) |
TW (1) | TW588034B (en) |
WO (1) | WO2000026181A1 (en) |
ZA (1) | ZA200103323B (en) |
Families Citing this family (6)
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CA2388816A1 (en) | 1999-11-16 | 2001-05-25 | Ciba Specialty Chemicals Holding Inc. | Process for the preparation of ketimines |
ES2241680T3 (en) | 1999-11-16 | 2005-11-01 | Ciba Specialty Chemicals Holding Inc. | PROCEDURE FOR THE PREPARATION OF CETIMINAS. |
US8076518B2 (en) | 2005-03-28 | 2011-12-13 | Albemarle Corporation | Chain extenders |
US7964695B2 (en) | 2005-03-28 | 2011-06-21 | Albemarle Corporation | Chain extenders |
EP1868987A1 (en) * | 2005-03-28 | 2007-12-26 | Albemarle Corporation | Diimines and secondary diamines |
TR200808115T1 (en) * | 2006-04-28 | 2009-03-23 | Sandoz Ag | Process for the Preparation of 4 (S, R) - (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] methylamine |
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GB1420472A (en) * | 1972-09-27 | 1976-01-07 | Pfizer | Aminophenyltetralin compounds |
IN191358B (en) * | 1998-01-16 | 2003-11-29 | Pfizer Prod Inc |
-
1999
- 1999-10-19 AU AU11525/00A patent/AU767324B2/en not_active Ceased
- 1999-10-19 EP EP99971411A patent/EP1124792B1/en not_active Expired - Lifetime
- 1999-10-19 HU HU0104323A patent/HUP0104323A3/en unknown
- 1999-10-19 ES ES99971411T patent/ES2226501T3/en not_active Expired - Lifetime
- 1999-10-19 AT AT99971411T patent/ATE272611T1/en not_active IP Right Cessation
- 1999-10-19 TR TR2001/00942T patent/TR200100942T2/en unknown
- 1999-10-19 CA CA002346900A patent/CA2346900A1/en not_active Abandoned
- 1999-10-19 JP JP2000579570A patent/JP2002528528A/en active Pending
- 1999-10-19 DE DE59910149T patent/DE59910149D1/en not_active Expired - Fee Related
- 1999-10-19 CN CN99812760A patent/CN1325381A/en active Pending
- 1999-10-19 PT PT99971411T patent/PT1124792E/en unknown
- 1999-10-19 IL IL14236799A patent/IL142367A0/en unknown
- 1999-10-19 WO PCT/EP1999/007894 patent/WO2000026181A1/en active IP Right Grant
- 1999-10-28 TW TW088118648A patent/TW588034B/en not_active IP Right Cessation
- 1999-10-28 AR ARP990105445A patent/AR021005A1/en not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
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CN1325381A (en) | 2001-12-05 |
EP1124792B1 (en) | 2004-08-04 |
IL142367A0 (en) | 2002-03-10 |
AU1152500A (en) | 2000-05-22 |
DE59910149D1 (en) | 2004-09-09 |
AR021005A1 (en) | 2002-06-05 |
EP1124792A1 (en) | 2001-08-22 |
ATE272611T1 (en) | 2004-08-15 |
JP2002528528A (en) | 2002-09-03 |
HUP0104323A2 (en) | 2002-08-28 |
TR200100942T2 (en) | 2001-08-21 |
PT1124792E (en) | 2004-12-31 |
WO2000026181A1 (en) | 2000-05-11 |
CA2346900A1 (en) | 2000-05-11 |
HUP0104323A3 (en) | 2002-11-28 |
AU767324B2 (en) | 2003-11-06 |
ES2226501T3 (en) | 2005-03-16 |
TW588034B (en) | 2004-05-21 |
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