NO774402L - R METHOD OF PREPARATION OF METHOXY BENZAMIDE DERIVATIVES - Google Patents
R METHOD OF PREPARATION OF METHOXY BENZAMIDE DERIVATIVESInfo
- Publication number
- NO774402L NO774402L NO774402A NO774402A NO774402L NO 774402 L NO774402 L NO 774402L NO 774402 A NO774402 A NO 774402A NO 774402 A NO774402 A NO 774402A NO 774402 L NO774402 L NO 774402L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- trifluoromethyl
- carbon atoms
- alkyl
- ether
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 6
- PBQZQTQFQFYBNJ-UHFFFAOYSA-N n-methoxybenzamide Chemical class CONC(=O)C1=CC=CC=C1 PBQZQTQFQFYBNJ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 34
- -1 2-Methoxy-benzoyl halide Chemical class 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- MNWSGMTUGXNYHJ-UHFFFAOYSA-N 2-methoxybenzamide Chemical class COC1=CC=CC=C1C(N)=O MNWSGMTUGXNYHJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000009835 boiling Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- SMSVMBMJEYTUOZ-UHFFFAOYSA-N 1-(4-fluoro-3-methylphenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C(C)=C1 SMSVMBMJEYTUOZ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- WZBPZYCJUADXRS-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 WZBPZYCJUADXRS-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- UUOVPAFAXSKGMP-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzamide Chemical compound NC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 UUOVPAFAXSKGMP-UHFFFAOYSA-N 0.000 description 3
- VOCCEVKUXUIHOI-UHFFFAOYSA-N 4-fluoro-3-methylbenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1F VOCCEVKUXUIHOI-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 230000000707 stereoselective effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YZIFVWOCPGPNHB-UHFFFAOYSA-N 1,2-dichloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C(Cl)=C1 YZIFVWOCPGPNHB-UHFFFAOYSA-N 0.000 description 2
- WNVZOHNNPDZYFN-UHFFFAOYSA-N 1,2-oxazole-3-carbaldehyde Chemical compound O=CC=1C=CON=1 WNVZOHNNPDZYFN-UHFFFAOYSA-N 0.000 description 2
- MMZYCBHLNZVROM-UHFFFAOYSA-N 1-fluoro-2-methylbenzene Chemical compound CC1=CC=CC=C1F MMZYCBHLNZVROM-UHFFFAOYSA-N 0.000 description 2
- GTKYLVJCMKDNTH-UHFFFAOYSA-N 2-methoxy-5-sulfamoylbenzamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(N)=O GTKYLVJCMKDNTH-UHFFFAOYSA-N 0.000 description 2
- XFZMCFJADJFEBB-UHFFFAOYSA-N 2-methoxy-5-sulfamoylbenzoyl chloride Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(Cl)=O XFZMCFJADJFEBB-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- LUWRKDCBHVRKOA-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzoyl fluoride Chemical compound FC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 LUWRKDCBHVRKOA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000012545 Psychophysiologic disease Diseases 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Chemical compound Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- OEYAFMGVIFWPQI-UHFFFAOYSA-N (1-benzylpyrrolidin-2-yl)methanamine Chemical compound NCC1CCCN1CC1=CC=CC=C1 OEYAFMGVIFWPQI-UHFFFAOYSA-N 0.000 description 1
- NREUBTUYADXMHQ-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(CCl)=CC=C1Cl NREUBTUYADXMHQ-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- SQAILWDRVDGLGY-UHFFFAOYSA-N 2-methoxy-5-sulfamoylbenzoic acid Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(O)=O SQAILWDRVDGLGY-UHFFFAOYSA-N 0.000 description 1
- XUWYBISTYZABLV-UHFFFAOYSA-N 2-methoxy-n-(pyrrolidin-2-ylmethyl)-5-sulfamoylbenzamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(=O)NCC1NCCC1 XUWYBISTYZABLV-UHFFFAOYSA-N 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- BIUDHHGROGJSHN-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzaldehyde Chemical compound FC1=CC=C(C=O)C=C1C(F)(F)F BIUDHHGROGJSHN-UHFFFAOYSA-N 0.000 description 1
- BUDISZQHCHGLJW-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1C(F)(F)F BUDISZQHCHGLJW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 208000012886 Vertigo Diseases 0.000 description 1
- HZDVQEUISWBXPV-UHFFFAOYSA-N [4-fluoro-3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(F)C(C(F)(F)F)=C1 HZDVQEUISWBXPV-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- GUNJVIDCYZYFGV-UHFFFAOYSA-K antimony trifluoride Chemical compound F[Sb](F)F GUNJVIDCYZYFGV-UHFFFAOYSA-K 0.000 description 1
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 229930188620 butyrolactone Natural products 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000002903 catalepsic effect Effects 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- CJXGPJZUDUOZDX-UHFFFAOYSA-N fluoromethanone Chemical group F[C]=O CJXGPJZUDUOZDX-UHFFFAOYSA-N 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 231100000029 gastro-duodenal ulcer Toxicity 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 230000001962 neuropharmacologic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N ortho-methoxybenzoic acid Natural products COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Description
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av 2-metoksy-benzamid-derivater i form av racemater eller enantiomerer, med den generelle formel (I) The present invention relates to a method for the production of 2-methoxy-benzamide derivatives in the form of racemates or enantiomers, with the general formula (I)
hvori in which
står for et kloratom,stands for a chlorine atom,
eller et radikal S02R5hvori R5er alkyl med 1 til 4 karbonatomer, or a radical SO 2 R 5 in which R 5 is alkyl of 1 to 4 carbon atoms,
eller et radikal S02NRgR7, hvori Rg og R7er like eller forskjellige og står for et hydrogenatom eller et alkyl-radikal med 1 til 4 karbonatomer, or a radical S02NRgR7, in which Rg and R7 are the same or different and represent a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms,
R2 står for et hydrogenatom eller alkyl med 1 til 4 karbonatomer, R2 stands for a hydrogen atom or alkyl with 1 to 4 carbon atoms,
R^ og R4står for et halogenatom eller trifluormetyl, trifluormetoksy, trifluormetyltio, alkoksy med 1 til 4 karbonatomer eller alkyl med 1 til 4 karbonatomer, og R 1 and R 4 stand for a halogen atom or trifluoromethyl, trifluoromethoxy, trifluoromethylthio, 1 to 4 carbon alkoxy or 1 to 4 carbon alkyl, and
R 5 står for et hydrogenatom eller et halogenatom eller trifluormetyl, trif luormetoksy, trifluormetyltio, alkoksy med 1 til 4 karbonatomer eller alkyl med 1 til 4 karbonatomer, R 5 stands for a hydrogen atom or a halogen atom or trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxy with 1 to 4 carbon atoms or alkyl with 1 to 4 carbon atoms,
såvel som salter derav med farmasbytisk tålbare syrer.as well as salts thereof with pharmaceutically acceptable acids.
Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at man omsetter et 2-metoksybenzoyl-halogenid med den generelle formel (II) The peculiarity of the method according to the invention is that one reacts a 2-methoxybenzoyl halide with the general formula (II)
hvori R^ har den ovennevnte betydning og X betyr et halogenatom, med et amin med formel (III) i form av racematet eller enantiomeren hvori R2, R2/ R4og R5har den ovennevnte betydning, eller et benzamid med formel (IV) i form av racematet eller enantiomeren med den generelle formel hvori og R 2 har den ovennevnte betydning, omsettes med en forbindelse med formel (V) in which R^ has the above meaning and X means a halogen atom, with an amine of formula (III) in the form of the racemate or enantiomer in which R 2 , R 2 / R 4 and R 5 have the above meaning, or a benzamide of formula (IV) in the form of the racemate or the enantiomer of the general formula wherein and R 2 has the above-mentioned meaning, is reacted with a compound of formula (V)
hvori R^, R4, R5 og X har den ovennevnte betydning, wherein R 1 , R 4 , R 5 and X have the above meaning,
idet om onsket, for fremstilling av forbindelser med formel I hvori R2er alkyl med 1 til 4 karbonatomer, underkastes erholdte forbindelser med formel I hvori R2 er hydrogen, for en alkylering. whereby, if desired, for the preparation of compounds of formula I in which R 2 is alkyl with 1 to 4 carbon atoms, the obtained compounds of formula I in which R 2 is hydrogen are subjected to an alkylation.
Benzylradikalet kan bære to eller tre substituenter, og de posisjoner som foretrekkes for tosubstituenter er 3-stillingen og 4-stillingen. The benzyl radical can carry two or three substituents, and the preferred positions for two substituents are the 3-position and the 4-position.
De ved fremgangsmåten i henhold til oppfinnelsen fremstillbare forbindelser inneholder et asymmetrisk karbonatom og kan da eksistere i form av racemater eller enantiomerer. The compounds which can be prepared by the method according to the invention contain an asymmetric carbon atom and can then exist in the form of racemates or enantiomers.
Forbindelsene kan .anvendes som human- eller veterinær-terapeutika, spesielt på området nervose og psykosomatiske lidelser. Fremgangsmåten utfores ved anvendelse av kjente metoder og man kan omsette et substituert 2-metoksy-benzosyrehalogenid med den generelle formel (El) med et amin med den generelle formel (EI3) i form av racematet eller enantiomeren The compounds can be used as human or veterinary therapeutics, especially in the area of nervous and psychosomatic disorders. The procedure is carried out using known methods and a substituted 2-methoxybenzoic acid halide of the general formula (E1) can be reacted with an amine of the general formula (EI3) in the form of the racemate or enantiomer
I de ovenstående formler (II) og (III) har R^ t R^>R4 °Q R5de samme betydninger som angitt for formel (I) og X betyr et halogen, spesielt klor eller brom. In the above formulas (II) and (III), R^ t R^>R4 °Q R5 have the same meanings as given for formula (I) and X means a halogen, especially chlorine or bromine.
Denne reaksjon gjennomfbres foretrukket ved lave temperaturerThis reaction is preferably carried out at low temperatures
(-5 til +30°C) i et lbsningsmiddel som f.eks. et keton og i nærvær av et alkalikarbonat. (-5 to +30°C) in a solvent such as e.g. a ketone and in the presence of an alkali carbonate.
Om onsket kan man fremstille forbindelser med formel (I) hvori R2står for alkyl, ved forst å fremstille amidet og deretter tilknytte alkylradikalet R^på nitrogenet ved alkylering. If desired, compounds of formula (I) in which R 2 stands for alkyl can be prepared by first preparing the amide and then attaching the alkyl radical R 2 to the nitrogen by alkylation.
Videre kan man tilknytte radikaletFurthermore, one can associate the radical
på nitrogenet i den heterocykliske kjerne ved reaksjon mellom forbindelser med formel (IV) i form av racematet eller enantiomeren hvori og R2har den ovennevnte betydning, med forbindelser med formel (V) on the nitrogen in the heterocyclic nucleus by reaction between compounds of formula (IV) in the form of the racemate or enantiomer in which and R2 has the above meaning, with compounds of formula (V)
hvori R^, R^og Rj. har den ovennevnte betydning og X står for et halogenatom. in which R^, R^ and Rj. has the above meaning and X stands for a halogen atom.
Utgangsforbindelsene med formel (CII) fremstilles på kjent måte, fordelaktig fra butyrolakton. The starting compounds of formula (CII) are prepared in a known manner, advantageously from butyrolactone.
Utgangsforbindelsene (IV) fremstilles ved debenzylering av den N-benzylerte forbindelse som oppnås ved kondensering mellom 2-metoksy-5-sulfamoyl-benzoylklorid og N-benzyl-2-aminometyl-pyrrolidin. The starting compounds (IV) are prepared by debenzylation of the N-benzylated compound which is obtained by condensation between 2-methoxy-5-sulfamoyl-benzoyl chloride and N-benzyl-2-aminomethyl-pyrrolidine.
Utgangsforbindelsene (V) kan fremstilles fra substituerte benzener ved kjente reaksjoner. The starting compounds (V) can be prepared from substituted benzenes by known reactions.
Blant forbindelsene (V) er forbindelsene med formel Among the compounds (V) are the compounds of formula
og de utgangsforbindelser som tjener til deres fremstilling nye forbindelser. Forbindelser med formel (VI) and the output compounds that serve for their production new compounds. Compounds of formula (VI)
hvori in which
R er cyano, formyl, hydroksymetyl, aminometyl, klormetyl, karboksy, fluorkarbonyl, klorkarbonyl, alkoksykarbonyl eller karbamoyl er nye forbindelser. R is cyano, formyl, hydroxymethyl, aminomethyl, chloromethyl, carboxy, fluorocarbonyl, chlorocarbonyl, alkoxycarbonyl or carbamoyl are new compounds.
Det etterfolgende reaksjonsskjema illustrerer fremstilling av disse forbindelser (VI) The following reaction scheme illustrates the production of these compounds (VI)
Forbindelsene har som nevnt et asymmetrisk karbonatom og oppdeling av forbindelsene gjennomfores ved hjelp av kbssiske metoder, f.eks. ved tilsetning til racematet av en omhyggelig valgt optisk aktiv syre hvoretter de derved oppnådde salter separeres på grunn av deres forskjellige loselighet i et valgt lbsningsmiddel. As mentioned, the compounds have an asymmetric carbon atom and division of the compounds is carried out using cubic methods, e.g. by adding to the racemate a carefully selected optically active acid, after which the salts thus obtained are separated due to their different solubility in a selected solvent.
Man kan også gjennomfore stereospesifikk syntese av forbindelsene (I), f.eks. ved at man på stereospesifikk måte syntetiserer en av de optiske isomerer av et pyrrolidin (III) som kondenseres med et 2-metoksy-benzoylhalogenid. One can also carry out stereospecific synthesis of the compounds (I), e.g. by stereospecifically synthesizing one of the optical isomers of a pyrrolidine (III) which is condensed with a 2-methoxy-benzoyl halide.
Det etterfolgende eksempel 3 illustrerer denne metode. The following example 3 illustrates this method.
Oppfinnelsen skal i det fblgende beskrives nærmere ved hjelp av spesifikke eksempler hvori smeltepunktene er bestemt på et Tottoli-apparat. Infrarbd og kjernemagnetisk resonansanalyse bekrefter strukturen av forbindelsene. In the following, the invention will be described in more detail with the help of specific examples in which the melting points are determined on a Tottoli apparatus. Infrared and nuclear magnetic resonance analysis confirm the structure of the compounds.
EKSEMPEL 1: N- { /l-(4-klor-3-trifluormetyl-benzyl)-2-pyrrolidi-nyl7-metyl} -2-metoksy-5-sulfamoyl-benzamid og dets metansulfonat EXAMPLE 1: N-{ /1-(4-chloro-3-trifluoromethyl-benzyl)-2-pyrrolidinyl-7-methyl}-2-methoxy-5-sulfamoyl-benzamide and its methanesulfonate
Til en opplbsning omrbrt under tilbakelbp av 12,5 g (0,04 mol) N-£-pyrrolidinyl)-2-metoksy-5-sulfamoyl-benzamid i 600 ml aceton tilsettes 7,5. g IC^CO^, 1 krystall av Kl, og deretter sakte i lbpet av 1 time 9,2 g (0,04 mol) 3-trifluormetyl-4-klor-benzyl-klorid i 150 ml aceton. 7.5 is added to a refluxing solution of 12.5 g (0.04 mol) of N-β-pyrrolidinyl)-2-methoxy-5-sulfamoyl-benzamide in 600 ml of acetone. g of IC^CO^, 1 crystal of Kl, and then slowly over 1 hour 9.2 g (0.04 mol) of 3-trifluoromethyl-4-chloro-benzyl chloride in 150 ml of acetone.
Deretter fortsettes oppvarmingen under tilbakelbp og omrbring iThe heating is then continued during return and rotation
3 timer. Det filtreres varmt og bunnfallet vaskes flere ganger med aceton. Etter avdamping av aceton til tbrrhet behandles resten med petroleter, vaskes to ganger hver gang med 150 ml eter og tbrkes maksimalt. 3 hours. It is filtered hot and the precipitate is washed several times with acetone. After evaporating the acetone to dryness, the residue is treated with petroleum ether, washed twice each time with 150 ml of ether and dried to the maximum.
Produktet omkrystalliseres fra aceton med behandling med plantekull. Produktet opplbses på nytt i aceton, tilsettes 5 ml konsentrert amoniakk og et stort overskudd av vann. Produktet utfelles, avsuges på filter, vaskes med vann, avsuges maksimalt på filteret og torkes i tbrkeskap til konstant vekt. The product is recrystallized from acetone with charcoal treatment. The product is re-dissolved in acetone, 5 ml of concentrated ammonia and a large excess of water are added. The product is precipitated, extracted on a filter, washed with water, extracted maximally on the filter and dried in a drying cabinet to a constant weight.
Det avsluttes med en omkrystallisering en gang fra metanol og en gang fra aceton. Produktet vaskes med eter og torkes i varm desikator. Det oppnådde produkt smelter ved 197 til 198°C. It ends with a recrystallization once from methanol and once from acetone. The product is washed with ether and dried in a hot desiccator. The product obtained melts at 197 to 198°C.
MetansulfonatMethanesulfonate
Basen i opplosning i aceton tilsettes en stbkiometrisk mengde metansulfonsyre. Saltet felles ut, avsuges påÆilter, vaskes med eter og omkrystalliseres fra metanol. Produktet torkes i varm desikator. The base in solution in acetone is added to a stobiometric amount of methanesulfonic acid. The salt is precipitated out, filtered off with suction, washed with ether and recrystallized from methanol. The product is dried in a hot desiccator.
Smp. = 214 - 215°C. Temp. = 214 - 215°C.
EKSEMPEL 2: N-^ /l-(4-fluoro-3-trifluormetyl-benzyl)-2-py r roi idi ny 1^-mety 1 j* - 2 -me t ok sy- 5 - sul f amoy 1 - ;benzamid og dets metansulfonat; ; 1. Fremstilling av utgangsforbindelser;1.1 3-trifluormetyl-4-fluoro-benzosyre (7), dens fluorid (6) og dens klorid (8). ;a) 3-metyl-4-fluor-acetofenon (II);I en 250 ml Erlenmeyer-kolbe innfores 36 g (0,33 mol) ortofluortoluen og 18,4 g (0,14 mol) aluminiumklorid. Det oppvarmes til 35°C og innfores dråpevis en opplosning av 8,8 g (0,11 mol) acetylklorid i 8 ml ortofluortoluen. Etter avsluttet tilsetning oppvarmes i 2 timer ved 35°C. Det avkjbles, hydrolyseres med en blanding av is og saltsyre, ekstraheres med eter, eterfasen torkes over MgS04, MgS04frafiltreres og eterfasen rektifiseres. ;Man oppnår overskuddet av ortofluoretylen med kokepunkt20= 35°c og oppnår det onskede 4-fluor-3-metyl-acetofenon. ;KokepunktQ Q1 = 68 - 70°C.;Denne forbindelse er tidligere beskrevet av BUU-HOI et JACQUIGNON, J. Chem. Soc. (1952) side 4173-5. ;b) 3-metyl-4-fluor-benzosyre (3) og dens klorid (4).;I en 10-liters reaktor avkjblt med en blanding av is og salt ;innfores 3 1 vann, 672 g NaOH og 1,51 kg knust is. Deretter innfores under kraftig omrbring ved temperatur mellom 0 og 10°C 352 ml brom. Temperaturen får stige til 22°C og i lbpet av 15 min. tilsettes 160 g 3-metyl-4-fluor-acetofenon (II). Deretter omrbres det ytterligere i 4 timer ved 24 - 25°C. Overskudd av hypobromitt spaltes med 60 ml natriumbisulfitt og det filtreres for å oppnå en klar lbsning. ;Det ekstraheres med eter og den vandige fase syres med konsentrert saltsyre hvorved syren utfelles. Den frafiltreres, vaskes med vann, avvannes på filter og torkes i desikator oppvarmet til 40°C under vakuum. ;Smp. 165 - 167°C. ;Denne forbindelse er tidligere beskrevet av BUU-HOI et JACQUIGNON, J. Chem. Soc. (1952) side 4173 - 5. ;Til 740 ml tionylklorid tilsettes under omrbring 346 g av syren (3) og 3 dråper pyridin. Deretter oppvarmes under tilbakelbp under omrbring i 4 timer. Tionylkloridet i overskudd avdampes og ved destillasjon under redusert trykk oppnås kloridet. ;Kokepunktiy = 129 - 133°C.;c) 3-trikloraretyl-4-fluor-benzoylklorid (5).;Til 50 g av syrekloridet (4) tilsettes 2,7 g PC15og det ;oppvarmes ved 190°C under omrdring. Deretter fores en strbm av klor gjennom opplbsningen. Man folger reaksjonen ved hjelp av kjernemagnetisk resonansanalyse. Ved avsluttet reaksjon (omtrent 40 timer) destilleres under redusert trykk.. Reaksjons-varigheten kan gjbres kortere ved bestråling med en UV-lampe. ;KokepunktQ ^ = 84°C.;d) 3-trifluormetyl-4-fluor-benzoylfluorid (6).;Til 12,5 g av syrekloridet (5) tilsettes 13 g SbF3og det ;oppvarmes under oppvarming til 70°C. Ved denne temperatur tilsettes 4 til 5 dråper SbCl5og blandingen oppvarmes hurtig til 220 til 230°C mens man lar fluss-syren avdestillere. ;Kokepunktlg = 57 - 60°C.;e) 3-trifluormetyl-4-fluor-benzosyre (7).;10 g av fluoridet (6) tilsettes til 150 ml vann. Det dannes et ;bunnfall som filtreres på glassfilter og bunnfallet vaskes med vann. Bunnfallet omrbres i 1 time i 20% NaOH. Ved tilsetning av konsentrert HC1 oppnås syren (7). ;Filtratet som inneholder en olje omrbres i 1 time med NaOH i overskudd. Ved surgjbring oppnås på nytt 3-trifluormetyl-4-fluor-benzosyren (7). ;Smp. 115 - 116°C. ;3-trifluormetyl-4-fluor-benzosyre kan likeledes oppnås ved å gå ut fra nitrilet (13) beskrevet i det etterfblgende. ;f) 3-trifluormetyl-4-fluor-benzoylklorid (8).;Under tilbakelbp og oppvarming oppvarmes i 2 timer 1,4 g (0,67 ;mol) av syren (7) med 2 ml tionylklorid og 1 dråpe pyridin. Tionylklorid i overskudd avdampes og resten loses i eter. Det filtreres, eter avdampes og det destilleres under redusert trykk fra en retorte. ;Kokepunkt6 = 80 - 90°C.;1.2 3-trifluormetyl-4-fluor-benzamid (12);Det rå syreklorid (8) tilsettes til en omrbrt konsentrert amoniakklbsning. Det omrbres i 1,5 time og produktene settes bort over natten. Det tilsettes 100 ml vann og blandingen settes under vakuum for å fjerne overskudd av amoniakk. Det filtreres deretter på glassfilter. Amidet opplbses på nytt i eter, torkes over MgS04, filtreres og inndampes til tbrrhet. Det omkrystalliseres to ganger fra petroleter inneholdende 15% eter. Det torkes i tbrkeskap ved 60°C. ;Smp. = 87 - 88°C.;Man kan også oppnå amidet (12) ved å gå ut fra 3-trifluormetyl-4-fluor-benzoylfluorid ved samme arbeidsmåte. ;Amidet kan også fremstilles ved å gå ut fra nitrilet (13) som er beskrevet i det etterfblgende. ;1.3 3-trifluormetyl-4-fluor-benzylamin (15).;Til 1,7 g LiAlH^i 50 ml vannfri eter under omrbring tilsettes sakte 2,5 g av amidet (12) i opplosning i 25 ml vannfri eter slik at det foregår en forsiktig tilbakelbpskoking. Deretter oppvarmer man i 4 timer under tilbakelbp og omrbring og blandingen settes bort over natten. Det avkjbles ved hjelp av et isblandet vannbad og hydrolyse foretas ved innfbring av et overskudd av en med eter, torkes over MgSO^, filtreres og inndampes til torrhet. Resten destilleres under redusert trykk. ;KokepunktQ 5 = 55 - 60°C.;1.6 l-hydroksymetyl-3-trifluormetyl-4-fluor-benzen (10);1. metode; Til 17,7 galdehyd^ (14) i 100 ml alkohol tilsettes under omrbring og avkjbling på et bad av isblandet vann 5 g NaBH^i lbpet av omtrent 10. min. Deretter omrbres i 1 time ved omgivelsenes temperatur og det inndampes til torrhet under redusert trykk (bad ved 50°C). Resten hydrolyseres med isblandet vann og surgjbres med 10% HC1. Det ekstraheres med eter, torkes over MgSO^, filtreres, og eter avdampes. Det oppnås en olje som er ren ved analyse (CCM). 2. metode; ;Til 0,55 g LiAlH4i 25 ml vannfri eter tilsettes ved forsiktig tilbakelbpskoking 1,7 g av esteren (9) i 10 ml eter. Deretter oppvarmes under tilbakelbp og omrbring i 3 timer. Etter avkjbling hydrolyseres med et overskudd av fortynnet NaOH-lbsning, bunnfallet filtreres på glassfilter og vaskes med eter og eterfasen torkes over MgSO^, filtreres, eter avdampes og alkoholen (10) destilleres under redusert trykk. ;Kokepunkt q1= 80~85°c*EXAMPLE 2: N-^ /l-(4-Fluoro-3-trifluoromethyl-benzyl)-2-pyrroiidiny 1^-methyl 1 j* - 2 -me t ok sy- 5 - sul f amoy 1 - ;benzamide and its methanesulfonate; ; 1. Preparation of starting compounds; 1.1 3-trifluoromethyl-4-fluoro-benzoic acid (7), its fluoride (6) and its chloride (8). ;a) 3-methyl-4-fluoro-acetophenone (II); 36 g (0.33 mol) orthofluorotoluene and 18.4 g (0.14 mol) aluminum chloride are introduced into a 250 ml Erlenmeyer flask. It is heated to 35°C and a solution of 8.8 g (0.11 mol) acetyl chloride in 8 ml of orthofluorotoluene is introduced dropwise. After the addition is finished, heat for 2 hours at 35°C. It is cooled, hydrolysed with a mixture of ice and hydrochloric acid, extracted with ether, the ether phase is dried over MgSO 4 , the MgSO 4 is filtered off and the ether phase is rectified. The excess of orthofluoroethylene with boiling point 20= 35°c is obtained and the desired 4-fluoro-3-methyl-acetophenone is obtained. ;Boiling point Q Q1 = 68 - 70°C.;This compound was previously described by BUU-HOI et JACQUIGNON, J. Chem. Soc. (1952) pp. 4173-5. ;b) 3-methyl-4-fluoro-benzoic acid (3) and its chloride (4).;In a 10-litre reactor cooled with a mixture of ice and salt ;introduce 3 1 of water, 672 g of NaOH and 1.51 kg crushed ice. 352 ml of bromine are then introduced under vigorous stirring at a temperature between 0 and 10°C. The temperature is allowed to rise to 22°C and within 15 min. 160 g of 3-methyl-4-fluoro-acetophenone (II) are added. It is then stirred for a further 4 hours at 24 - 25°C. Excess hypobromite is digested with 60 ml of sodium bisulphite and filtered to obtain a clear solution. It is extracted with ether and the aqueous phase is acidified with concentrated hydrochloric acid, whereby the acid is precipitated. It is filtered off, washed with water, dewatered on a filter and dried in a desiccator heated to 40°C under vacuum. ; 165 - 167°C. This compound was previously described by BUU-HOI et JACQUIGNON, J. Chem. Soc. (1952) page 4173 - 5. 346 g of the acid (3) and 3 drops of pyridine are added with stirring to 740 ml of thionyl chloride. It is then heated under reflux with stirring for 4 hours. The thionyl chloride in excess is evaporated and the chloride is obtained by distillation under reduced pressure. Boiling point = 129 - 133°C.;c) 3-trichloroethyl-4-fluoro-benzoyl chloride (5).;To 50 g of the acid chloride (4), 2.7 g of PC15 is added and it is heated at 190°C with stirring. A stream of chlorine is then fed through the solution. The reaction is followed using nuclear magnetic resonance analysis. At the end of the reaction (approximately 40 hours) it is distilled under reduced pressure. The reaction duration can be shortened by irradiation with a UV lamp. ;Boiling point Q ^ = 84°C.;d) 3-trifluoromethyl-4-fluoro-benzoyl fluoride (6).;To 12.5 g of the acid chloride (5) is added 13 g of SbF3 and it is heated under heating to 70°C. At this temperature, 4 to 5 drops of SbCl5 are added and the mixture is heated rapidly to 220 to 230°C while allowing the hydrofluoric acid to distill off. ;Boiling point = 57 - 60°C.;e) 3-trifluoromethyl-4-fluoro-benzoic acid (7).;10 g of the fluoride (6) is added to 150 ml of water. A precipitate is formed which is filtered on a glass filter and the precipitate is washed with water. The precipitate is stirred for 1 hour in 20% NaOH. By adding concentrated HC1, the acid (7) is obtained. The filtrate containing an oil is stirred for 1 hour with excess NaOH. Upon acidification, 3-trifluoromethyl-4-fluoro-benzoic acid (7) is obtained again. ; 115 - 116°C. ;3-trifluoromethyl-4-fluoro-benzoic acid can likewise be obtained by starting from the nitrile (13) described in the following. f) 3-trifluoromethyl-4-fluorobenzoyl chloride (8). Under reflux and heating, 1.4 g (0.67 mol) of the acid (7) are heated for 2 hours with 2 ml of thionyl chloride and 1 drop of pyridine. Excess thionyl chloride is evaporated and the residue dissolved in ether. It is filtered, the ether is evaporated and it is distilled under reduced pressure from a retort. ;Boiling point6 = 80 - 90°C.;1.2 3-trifluoromethyl-4-fluoro-benzamide (12);The crude acid chloride (8) is added to a stirred concentrated ammonia solution. It is stirred for 1.5 hours and the products are put away overnight. 100 ml of water is added and the mixture is placed under vacuum to remove excess ammonia. It is then filtered on a glass filter. The amide is redissolved in ether, dried over MgSO4, filtered and evaporated to dryness. It is recrystallized twice from petroleum ether containing 15% ether. It is dried in an oven at 60°C. ; = 87 - 88°C.; The amide (12) can also be obtained by starting from 3-trifluoromethyl-4-fluoro-benzoyl fluoride using the same working method. The amide can also be prepared by starting from the nitrile (13) which is described below. ;1.3 3-trifluoromethyl-4-fluoro-benzylamine (15).;To 1.7 g of LiAlH^ in 50 ml of anhydrous ether, while stirring, slowly add 2.5 g of the amide (12) in solution in 25 ml of anhydrous ether so that a careful back-boiling takes place. It is then heated for 4 hours under reflux and stirring and the mixture is set aside overnight. It is cooled using an ice-mixed water bath and hydrolysis is carried out by introducing an excess of one with ether, dried over MgSO^, filtered and evaporated to dryness. The remainder is distilled under reduced pressure. ;Boiling point Q 5 = 55 - 60°C.;1.6 l-Hydroxymethyl-3-trifluoromethyl-4-fluoro-benzene (10);1. method; To 17.7 galaldehyde^ (14) in 100 ml of alcohol, 5 g of NaBH^ are added over approximately 10 min while stirring and cooling in a bath of ice-mixed water. It is then stirred for 1 hour at ambient temperature and evaporated to dryness under reduced pressure (bath at 50°C). The residue is hydrolysed with ice-mixed water and acidified with 10% HC1. It is extracted with ether, dried over MgSO 4 , filtered, and the ether is evaporated. An oil that is pure by analysis (CCM) is obtained. 2nd method; ;To 0.55 g of LiAlH4 in 25 ml of anhydrous ether, 1.7 g of the ester (9) in 10 ml of ether are added by careful reflux. It is then heated under reflux and stirring for 3 hours. After cooling, hydrolyze with an excess of dilute NaOH solution, the precipitate is filtered on a glass filter and washed with ether and the ether phase is dried over MgSO^, filtered, the ether is evaporated and the alcohol (10) is distilled under reduced pressure. ;Boiling point q1= 80~85°c*
1.7 l-klormetyl-3-trifluormetyl-4-fluor-benzen (11)1.7 l-Chloromethyl-3-trifluoromethyl-4-fluoro-benzene (11)
Til en omrbrt lbsning under tilbakelbp av 17,7 g alkohol (10)To a refluxed solution of 17.7 g of alcohol (10)
i 120 ml benzen tilsettes 25 ml tionylklorid. Deretter oppvarmes under tilbakelbp og omrbring til fullstendig reaksjon (reaksjonen fblges ved CCM silika^CH2Cl2) varighet 70 timer (fra tid til annen tilsettes en dråpe pyridin eller alternativt en dråpe DMF). 25 ml of thionyl chloride are added to 120 ml of benzene. It is then heated under reflux and conversion to complete reaction (the reaction is followed by CCM silica^CH2Cl2) for 70 hours (from time to time a drop of pyridine or alternatively a drop of DMF is added).
Benzen avdestilleres og resten destilleres under redusert trykk. The benzene is distilled off and the residue is distilled under reduced pressure.
Kokepunkt2= 71°C.Boiling point2= 71°C.
1.8 3-trifluormetyl-4jj.fluor-etylbenzoat (9)1.8 3-trifluoromethyl-4jj.fluoro-ethylbenzoate (9)
2 g av syrekloridet (8) tilsettes til en omrbrt opplosning av2 g of the acid chloride (8) is added to a stirred solution of
50 ml abs. alkohol under tilbakelbp. Det oppvarmes under tilbakelbp i 30 min. og inndampes til torrhet ved atmosfæretrykk. Man destillerer under redusert trykk fra en retorte. 50 ml abs. alcohol under return lbp. It is heated under reflux for 30 min. and evaporated to dryness at atmospheric pressure. One distills under reduced pressure from a retort.
KokepunktQ 2 = 85 - 90°C.Boiling point Q 2 = 85 - 90°C.
2. Forbindelse ( I) 2. Connection ( I)
N-(2-pyrrolidinyl)-metyl-2-metoksy~5-sulfamoyl-benzamid og 3-trifluormetyl-4-fluor-benzylklorid omsettes under de samme betingelser som i eksempel 1. Man oppnår den tilsiktede forbindelse med smp. 188 - 189°C. Metansulfonatet har et smp. 233 - 234°C. N-(2-pyrrolidinyl)-methyl-2-methoxy-5-sulfamoyl-benzamide and 3-trifluoromethyl-4-fluoro-benzyl chloride are reacted under the same conditions as in example 1. The intended compound is obtained with m.p. 188 - 189°C. The methanesulfonate has a m.p. 233 - 234°C.
EKSEMPEL 3 : N- { /l- (3-trif luormetyl-4-f luor-benzyl) -2-pyrrolidinyl7-méyl^ -2-metoksy-5-sulfamoyl-benzamid ( R) (+) og dets metansulfonat ( R) (-) EXAMPLE 3 : N-{ /1-(3-trifluoromethyl-4-fluoro-benzyl)-2-pyrrolidinyl-7-methyl-2-methoxy-5-sulfamoyl-benzamide ( R ) (+) and its methanesulfonate ( R ) (-)
1. Total stereospesifikk syntese 1. Total Stereospecific Synthesis
Reaksjonsskjema (se etterfblgende side)Reaction form (see following page)
Trinn 1; 1-(3-trifluormetyl-4-fluor-benzyl)-2-okso-pyrrolidin-5-karboksylsyre (R) (-) Step 1; 1-(3-trifluoromethyl-4-fluoro-benzyl)-2-oxo-pyrrolidine-5-carboxylic acid (R) (-)
I en Erlenmeyer-kolbe innfores 27,6 g (0,187 mol) glutaminsyre (R) og 187 ml NaOH (2N). Under nitrogenstrbm tilsettes dråpevis 26 g (0,187 mol) 4-fluor-3-trifluormetyl-benzaldehyd i metanol. Det omrbres ved omgivelsenes temperatur i 1 dbgn og blandingen settes bort over natten. 27.6 g (0.187 mol) of glutamic acid (R) and 187 ml of NaOH (2N) are introduced into an Erlenmeyer flask. Under nitrogen pressure, 26 g (0.187 mol) of 4-fluoro-3-trifluoromethyl-benzaldehyde in methanol are added dropwise. It is stirred at ambient temperature for 1 hour and the mixture is set aside overnight.
Opplbsningen hydrogeneres under atmosfæretrykk og ved omgivelsenes trykk med katalysator Pd/C. Etter at det teoretiske hydrogenvolum er absorbert frafiltreres katalysatoren og metanol avdampes. Den vandige lbsning isoleres og ekstraheres med eter. Den vandige lbsning tilsettes saltsyre (IN) til pH = 4. Det hvite faststoff som er utfelt frafiltreres. Faststoffet blandes med vann og innstilles til pH 2,5. Det oppvarmes ved 100°C i 2 timer. Det avkjdles og produktet krystalliserer. Det filtreres, oppldses i kloroform og torkes over magnesiumsulfat. Den organiske fase konsentereres og det isoleres en olje som krystalliseres fra cykloheksan. Det avsuges på filter og torkes. Det oppnås det tilsiktede produkt som smelter ved 100 - 101°C. The solution is hydrogenated under atmospheric pressure and at ambient pressure with catalyst Pd/C. After the theoretical volume of hydrogen has been absorbed, the catalyst is filtered off and methanol is evaporated. The aqueous solution is isolated and extracted with ether. Hydrochloric acid (IN) is added to the aqueous solution to pH = 4. The white solid that has precipitated is filtered off. The solid is mixed with water and adjusted to pH 2.5. It is heated at 100°C for 2 hours. It is cooled and the product crystallizes. It is filtered, dissolved in chloroform and dried over magnesium sulphate. The organic phase is concentrated and an oil is isolated which is crystallized from cyclohexane. It is extracted on a filter and dried. The intended product is obtained which melts at 100 - 101°C.
IR og kjernemagnetisk resonansanalyse bekrefter strukturen.IR and nuclear magnetic resonance analysis confirm the structure.
Reaksjonsskjemaet for 1. trinn er gjengitt i det fdlgende. Bare det endelige produkt, den tilsiktede syre, isoleres. The reaction form for the 1st step is reproduced below. Only the final product, the intended acid, is isolated.
Trinn 2; 1-(trifluormetyl-4-fluor-benzyl)-2-okso-pyrrolidin-5-metylkarboksylat (R) Step 2; 1-(Trifluoromethyl-4-fluoro-benzyl)-2-oxo-pyrrolidine-5-methylcarboxylate (R)
I en Erlenmeyer-kolbe innfores 40 g (0,131 mol) av 1-(4-fluor-3-trifluormetyl-benzyl)-2-okso-pyrrolidin-5-karboksylsyre (R) og 100 ml metanol. Det oppvarmes ved 40°C og innfores dråpevis 18,7 g (0,157 mol) tionylklorid. Det oppvarmes under tilbakeldp i 4 timer. 40 g (0.131 mol) of 1-(4-fluoro-3-trifluoromethyl-benzyl)-2-oxo-pyrrolidine-5-carboxylic acid (R) and 100 ml of methanol are introduced into an Erlenmeyer flask. It is heated at 40°C and 18.7 g (0.157 mol) of thionyl chloride are introduced dropwise. It is heated under reflux for 4 hours.
Det inndampes til torrhet og det oppnås en oljeaktig rest som destilleres. It is evaporated to dryness and an oily residue is obtained which is distilled.
KokepunktQ Q5 = 130°CBoiling pointQ Q5 = 130°C
Den destillerte olje krystalliserer ved omgivelsenes temperatur. The distilled oil crystallizes at ambient temperature.
Smp. =60,5 - 61°C. Temp. =60.5 - 61°C.
Kjernemagnetisk resonans spektrum RMN bekrefter strukturen. Nuclear magnetic resonance spectrum RMN confirms the structure.
Trinn 3; 1-(3-trifluormetyl-4-fluor-benzyl)-2-oksopyrrolidin Step 3; 1-(3-trifluoromethyl-4-fluoro-benzyl)-2-oxopyrrolidine
5-karboksamid (R) (-)5-carboxamide (R) (-)
I en 1-liters Erlenmeyer-kolbe innfores 400 ml metanol og oppløsningen mettes med ammoniakk under avkjbling på is. Det innfores 35,8 g (0,112 mol) 1-(4-fluor-3-trifluormetyl-benzyl)-2-okso-pyrrolidin-5-metylkarboksylat (R) og det omrbres i 8 timer ved omgivelsenes temperatur. 400 ml of methanol are introduced into a 1-litre Erlenmeyer flask and the solution is saturated with ammonia while cooling on ice. 35.8 g (0.112 mol) of 1-(4-fluoro-3-trifluoromethyl-benzyl)-2-oxo-pyrrolidine-5-methylcarboxylate (R) are introduced and the mixture is stirred for 8 hours at ambient temperature.
Det inndampes til torrhet og oppnås et faststoff som omkrystalliseres fra aceton. It is evaporated to dryness and a solid is obtained which is recrystallized from acetone.
Smp. 204,5 - 20 5°C. Temp. 204.5 - 205°C.
RMN-spektralanalyse bekrefter strukturen. RMN spectral analysis confirms the structure.
Trinn 4: 1-(3-trifluormetyl-4-fluor-benzyl)-2-aminometyl-pyrrolidin (R) Step 4: 1-(3-trifluoromethyl-4-fluoro-benzyl)-2-aminomethyl-pyrrolidine (R)
I en Erlenmeyer-kolbe innfores 300 ml vannfri eter og under nitrogenstrom tilsettes 12,5 g (0,328 mol) av dobbelthydridet av litium og aluminium. 300 ml of anhydrous ether are introduced into an Erlenmeyer flask and 12.5 g (0.328 mol) of the double hydride of lithium and aluminum are added under a stream of nitrogen.
Det innfores deretter 25 g (0,0821 mol) av det ovennevnte amid25 g (0.0821 mol) of the above-mentioned amide are then introduced
i små porsjoner og det oppvarmes under tilbakelbp i 16 timer. in small portions and it is heated under reflux for 16 hours.
Det hydrolyseres med en lbsning av 10% av dobbelttartratet av natrium og kalium. Faststoffet frafiltreres og vaskes med eter. Eterfåsene slås sammen og inndampes. Det oppnås en olje som destilleres. It is hydrolysed with a solution of 10% of the double tartrate of sodium and potassium. The solid is filtered off and washed with ether. The ether phases are combined and evaporated. An oil is obtained which is distilled.
KokepunktQ 05 = 88°C.Boiling point Q 05 = 88°C.
Strukturen bekreftes av analyser IR og RMN.The structure is confirmed by analyzes IR and NMR.
Trinn 5; N- •[ /l- (3-trif luormetyl-4-f luor-benzyl) -2-pyrrolidinyl7-metyl^. 2-metoksy-5-sulf amoyl-benzamid (R) og dets metansulfonat (R) Step 5; N-•[ /1-(3-trifluoromethyl-4-fluoro-benzyl)-2-pyrrolidinyl-7-methyl^. 2-Methoxy-5-sulfamoyl-benzamide (R) and its methanesulfonate (R)
I en Erlenmeyer-kolbe innfores 13 g (0,054 mol) av det ovennevnte amin, 7,5 g (0,054 mol) kaliumkarbonat og 100 ml aceton. 13 g (0.054 mol) of the above-mentioned amine, 7.5 g (0.054 mol) potassium carbonate and 100 ml acetone are introduced into an Erlenmeyer flask.
Under avkjbling (t ^ 10°C) og under nitrogenstrom innfores dråpevis 13,4 g (0,054 mol) 2-metoksy-5-sulfamoyl-benzosyre i aceton. Det omrbres ved denne temperatur i 2 timer. Deretter inndampes til torrhet, resten opptas i vann og eter og uopplbselig substans frafiltreres. Den uopplbselige substans opplbses i kloroform og torkes over magnesiumsulfat. Det inndampes til torrhet,og oppnås den tilsiktede forbindelse som omkrystalliseres fra en blanding isopropyleter/isopropylalkohol. While cooling (t < 10°C) and under a stream of nitrogen, 13.4 g (0.054 mol) of 2-methoxy-5-sulfamoyl-benzoic acid in acetone are introduced dropwise. It is stirred at this temperature for 2 hours. It is then evaporated to dryness, the residue is taken up in water and ether and the insoluble substance is filtered off. The insoluble substance is dissolved in chloroform and dried over magnesium sulphate. It is evaporated to dryness, and the intended compound is obtained, which is recrystallized from an isopropyl ether/isopropyl alcohol mixture.
Etter eluering med etylacetat i silikagelkolonne oppnås etter avdamping et faststoff som omkrystalliseres fra en blanding i sopropylet er/i sopropylalkohol. After elution with ethyl acetate in a silica gel column, a solid is obtained after evaporation which is recrystallized from a mixture in isopropyl alcohol.
Smp. 144 - 145°C. Temp. 144 - 145°C.
Metansulfonat Methanesulfonate
I en Erlenmeyer-kolbe innfores 2,6 g (0,0053 mol) av basen i aceton og det tilsettes 0,5 g (0,0053 mol) metansulfonsyre. In an Erlenmeyer flask, introduce 2.6 g (0.0053 mol) of the base in acetone and add 0.5 g (0.0053 mol) of methanesulfonic acid.
I lbpet av noen minutter utfelles saltet som vaskes med aceton og torkes. After a few minutes, the salt precipitates, which is washed with acetone and dried.
F = 182,5 - 183°C. F = 182.5 - 183°C.
2. Kondensering 2. Condensation
Trinn 1 N-/2-pyrrolidinylmety2,7-2-metoksy-5-sulf amoylbenzamid og dets hydroklorid (R) (-) Step 1 N-(2-pyrrolidinylmethyl2,7-2-methoxy-5-sulfamoylbenzamide and its hydrochloride (R) (-)
N-/1 -benzyl -£-pyrrolidinyl) -mety^-2-metoksy-5-sulfamoylbenzamid (R) (+) debenzyleres, N-[1-benzyl ((-pyrrolidinyl)-methyl-2-methoxy-5-sulfamoylbenzamide (R) (+) is debenzylated,
oppnådd enten ved stereospesifikk syntese ved å gå ut fra 2-metoksy-5-sulfamoylbenzosyreklorid og l-benzyl-2-aminometyl-pyrrolidin (R) (+) eller ved oppspalting av racemisk N-/"(l-benzyl-2-pyrrolidinyl)metyl7metoksy-2-5-sulf amoylbenzamid ved hjelp av dibenzoylvinsyre D. obtained either by stereospecific synthesis starting from 2-methoxy-5-sulfamoylbenzoic acid chloride and l-benzyl-2-aminomethyl-pyrrolidine (R) (+) or by cleavage of racemic N-/"(l-benzyl-2-pyrrolidinyl )methyl7methoxy-2-5-sulfamoylbenzamide using dibenzoyltartaric acid D.
For dette anbringes i en autoklav på 1 1 34,8 g av den benzylerte forbindelse, 800 cm 3eddiksyre og 7,5 g 10% palladium på karbon. For this, 34.8 g of the benzylated compound, 800 cm 3 of acetic acid and 7.5 g of 10% palladium on carbon are placed in an autoclave.
Det gjennomfbres en hydrogenering under trykk 90 kg/cm 2ved 100°C i 12 timer, deretter avsuges katalysatoren på filter og eddiksyren avdampes. Den viskose rest opptas i etanol og tilsettes et overskudd av saltsyreholdig alkohol under omrbring. Et hvitt faststoff utkrystalliseres meget hurtig. Etter omrbring ved svak temperatur avkjbles og faststoffet avsuges på filter og torkes. A hydrogenation is carried out under pressure 90 kg/cm 2 at 100°C for 12 hours, then the catalyst is suctioned off on a filter and the acetic acid is evaporated. The viscous residue is taken up in ethanol and an excess of hydrochloric acid-containing alcohol is added with stirring. A white solid crystallizes out very quickly. After stirring at a low temperature, switch off and the solids are sucked off on a filter and dried.
Ved omkrystallisering fra etanol med litt metanol under tilbakelbp og avsuging oppnås et hvitt faststoff. A white solid is obtained by recrystallization from ethanol with a little methanol under reflux and suction.
Trinn 2 N- | /I-(4-fluor-3-trifluormetyl-3-benzyl)-2-pyrrolidinyl/metylj"2-metoksy-5-sulfamoylbenzamid (R) (+) og dets metansulfonat (R) (-) 1. I en Erlenmeyer-kolbe innfores 42,8 g (0,136 mol) 2- metoksy-5-sulfamoyl-N-(2-pyrrolidinylmetyl)benzamid (R) (-), 18,8 g (0,136 mol) kaliumkarbonat, noen krystaller av kaliumjodid og acetonitril. Det tilsettes dråpevis 29,1 g (0,136 mol) 3- trifluormetyl-4-fluor-benzylklorid og det oppvarmes under tilbakelbp i 8 timer. Det inndampes til torrhet og resten opptas i en blanding vann/eter og produktet filtreres, opplbses i kloroform, torkes over magnesiumsulfat og den organiske fase inndampes. Step 2 N- | /I-(4-Fluoro-3-trifluoromethyl-3-benzyl)-2-pyrrolidinyl/methylj"2-methoxy-5-sulfamoylbenzamide (R) (+) and its methanesulfonate (R) (-) 1. In an Erlenmeyer -flask are introduced 42.8 g (0.136 mol) 2-methoxy-5-sulfamoyl-N-(2-pyrrolidinylmethyl)benzamide (R) (-), 18.8 g (0.136 mol) potassium carbonate, some crystals of potassium iodide and acetonitrile 29.1 g (0.136 mol) of 3-trifluoromethyl-4-fluoro-benzyl chloride is added dropwise and it is heated under reflux for 8 hours. It is evaporated to dryness and the residue is taken up in a water/ether mixture and the product is filtered, dissolved in chloroform , dried over magnesium sulphate and the organic phase evaporated.
Det oppnås et faststoff som omkrystalliseres fra en blanding eter/i sopropylalkohol. 2. I en Erlenmeyer-kolbe innfores 57,3 g (0,117 mol) av basen opplost i aceton, og tilsettes 11,25 g (0,117 mol) metansulfonsyre i aceton. A solid is obtained which is recrystallized from an ether/isopropyl alcohol mixture. 2. In an Erlenmeyer flask, introduce 57.3 g (0.117 mol) of the base dissolved in acetone, and add 11.25 g (0.117 mol) methanesulfonic acid in acetone.
Det utfelles et hvitt faststoff som filtreres og torkes. EKSEMPEL 4 N- ^/l-(3,4-diklor-benzyl)-2-pyrrolidinyl7metyl5 -2-metoksy- 5- sulfamoyl- benzamid og dets metansulf onat Basen oppnås ved reaksjon mellom 3,4-diklor-benzylkloridet som fåes i handelen og N-/"(2-pyrrolidinyl)-mety3l7-2-metoksy-5-sulfamoyl-benzamidet, i aceton og i nærvær av kaliumkarbonat. A white solid is precipitated which is filtered and dried. EXAMPLE 4 N-^/l-(3,4-Dichloro-benzyl)-2-pyrrolidinyl-7-methyl-5-2-methoxy-5-sulfamoyl-benzamide and its methanesulfonate The base is obtained by reaction between the 3,4-dichloro-benzyl chloride obtained in the trade and the N-(2-pyrrolidinyl)-methyl317-2-methoxy-5-sulfamoyl-benzamide, in acetone and in the presence of potassium carbonate.
Til en omrort suspensjon under tilbakelbp av 12,5 g (0,04 mol) N-/"(2-pyrrolidinyl)-metyl7-2-metoksy-sulf amoylbenzamid i 600 ml aceton inneholdende 7,5 g I^CO^og en krystall av Kl, tilsettes i lbpet av 2 timer en opplosning av 8 g 3,4-diklorbenzylklorid i 200 ml aceton. Blandingen bringes til tilbakelbp i 2 timer, filtreres varm og bunnfallet vaskes med kokende aceton. Det inndampes til torrhet og resten behandles på glassfilter med petroleter. Det vaskes med petroleter og torkes i tbrkeskap. Bunnfallet opplbses på nytt i 350 ml aceton og 75 ml konsentrert ammoniakk. Det behandles med plantekull, filtreres og konsentreres til omtrent 250 mlc Volumet suppleres til 1200 ml med vann. Produktet utfelles og det filtreres på glassfilter, vaskes med vann, avsuges påÆilter og torkes i tbrkeskap. To a stirred suspension under reflux of 12.5 g (0.04 mol) N-/(2-pyrrolidinyl)-methyl7-2-methoxy-sulfamoylbenzamide in 600 ml of acetone containing 7.5 g of I^CO^ and a crystal of Kl, a solution of 8 g of 3,4-dichlorobenzyl chloride in 200 ml of acetone is added over the course of 2 hours. The mixture is brought to reflux for 2 hours, filtered hot and the precipitate is washed with boiling acetone. It is evaporated to dryness and the residue treated on glass filter with petroleum ether. It is washed with petroleum ether and dried in a fume hood. The precipitate is redissolved in 350 ml of acetone and 75 ml of concentrated ammonia. It is treated with charcoal, filtered and concentrated to approximately 250 ml. The volume is made up to 1200 ml with water. The product is precipitated and it is filtered on a glass filter, washed with water, suctioned onto a filter and dried in a drying cabinet.
Produktet opplbses på nytt i 450 ml kokende alkohol, behandles med kull, filtreres og konsentreres til et volum på 200 ml. Produktet krystalliserer. Det avsuges på glassfilter, vaskes med alkohol og eter, avsuges på filter og torkes i tbrkeskap. The product is redissolved in 450 ml of boiling alcohol, treated with charcoal, filtered and concentrated to a volume of 200 ml. The product crystallizes. It is extracted on a glass filter, washed with alcohol and ether, extracted on a filter and dried in an oven.
Smp. = 180 - 181°C. Temp. = 180 - 181°C.
MetansulfonatMethanesulfonate
Til 7,6 g av basen i opplosning i 600 ml kloroform og 50 ml metanol tilsettes 1,6 metansulfonsyre. Saltet krystalliseres. Det avsuges på glassfilter, avvannes og torkes i tbrkeskap. To 7.6 g of the base in solution in 600 ml of chloroform and 50 ml of methanol is added 1.6 methanesulfonic acid. The salt crystallizes. It is extracted on a glass filter, dewatered and dried in a drying cabinet.
Ved omkrystallisering fra metanol, vasking med eter, avsuging på filter og tbrking i varm desikator oppnås metansulfonatet med smp. 201 - 202°C. By recrystallization from methanol, washing with ether, suction on a filter and drying in a hot desiccator, the methanesulfonate is obtained with m.p. 201 - 202°C.
I den etterfølgende tabell I er angitt relative data for forbindelsene fra eksemplene. Forbindelsene fremstilt i henhold til oppfinnelsen ble underkastet farmakologiske forsbk som viser deres interessante psykotrope egenskaper. Forbindelsene ble tilfort i form av deres metansulfonater. In the subsequent table I, relative data for the compounds from the examples are given. The compounds produced according to the invention were subjected to pharmacological tests which show their interesting psychotropic properties. The compounds were supplied in the form of their methanesulfonates.
Akutt toksisitet ble bedbmt med hanmus av stammen Swiss CD 1 med midlere vekt 20 g. Acute toxicity was assessed with male mice of the strain Swiss CD 1 with an average weight of 20 g.
Den nevrofarmakologiske virkning ble undersbkt ved hjelp av fblgende to prover: 1) apomorfinantagonisme i hanmus av stammen Swiss CD 1 med midlere vekt 20 g, i henhold til/hetoden til Puech A, (Europ. The neuropharmacological effect was examined using the following two tests: 1) apomorphine antagonism in male mice of the strain Swiss CD 1 with an average weight of 20 g, according to the method of Puech A, (Europ.
J. Pharmacol. 1976, 36, 439).J. Pharmacol. 1976, 36, 439).
2) kataleptisk virkning i hanrotter av stammen Sprague Dawley (Charles River) med vekt 130 g i henhold til metoden til Tedeschi et Coll. (Arch. Intern. Pharmacodyn. 1959, 122, 129), (aktivitet forutsett mot nevrologiske lidelser av ekstrapyramidal opprinnelse i mennesker). 2) cataleptic action in male Sprague Dawley (Charles River) rats weighing 130 g according to the method of Tedeschi et Coll. (Arch. Intern. Pharmacodyn. 1959, 122, 129), (activity predicted against neurological disorders of extrapyramidal origin in humans).
Ved disse to prover ble resultatene uttrykt som 50% aktive doser (AD 50). For these two samples, the results were expressed as 50% active doses (AD 50).
Resultatene er samlet i den etterfblgende tabell II. The results are collected in the following table II.
Undersøkelsene av de foregående resultater viser at forbindelsene kan anvendes ved behandling av forskjellige psykosomatiske lidelser, som gastro-duodenale sår, migrene, vertigo, ved depressive og psykiske lidelser, spesielt ved eldre mennesker, og i stbrre doser ved psykoser, ut fra forbindelsenes nevroleptiske egenskaper uten sekundære virkninger. The investigations of the previous results show that the compounds can be used in the treatment of various psychosomatic disorders, such as gastro-duodenal ulcers, migraine, vertigo, in depressive and mental disorders, especially in elderly people, and in larger doses in psychoses, based on the compounds' neuroleptic properties without secondary effects.
Forbindelsene kan innfores i vanlige preparatformer enten ved oral, endorektal eller parenteral tilforsel. The compounds can be introduced in usual preparation forms either by oral, endorectal or parenteral administration.
Totaldose kan utgjore fra 5 til 300 mg. The total dose can range from 5 to 300 mg.
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7639034A FR2378520A1 (en) | 1976-12-24 | 1976-12-24 | N-1-enzyl-2-pyrrolidinyl-methyl 2-methoxy-benzamide derivs. - esp. the 5-sulphamoyl-benzamide cpds., are psychotropics and neuroleptics |
FR7639033A FR2375167A1 (en) | 1976-12-24 | 1976-12-24 | N-1-enzyl-2-pyrrolidinyl-methyl 2-methoxy-benzamide derivs. - esp. the 5-sulphamoyl-benzamide cpds., are psychotropics and neuroleptics |
Publications (1)
Publication Number | Publication Date |
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NO774402L true NO774402L (en) | 1978-06-27 |
Family
ID=26219761
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Application Number | Title | Priority Date | Filing Date |
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NO774402A NO774402L (en) | 1976-12-24 | 1977-12-21 | R METHOD OF PREPARATION OF METHOXY BENZAMIDE DERIVATIVES |
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JP (1) | JPS5382771A (en) |
AU (1) | AU3192177A (en) |
DE (1) | DE2757406A1 (en) |
DK (1) | DK575877A (en) |
ES (1) | ES465366A2 (en) |
FI (1) | FI773911A (en) |
GB (1) | GB1556566A (en) |
GR (1) | GR66082B (en) |
IL (1) | IL53680A0 (en) |
LU (1) | LU78773A1 (en) |
NL (1) | NL7714301A (en) |
NO (1) | NO774402L (en) |
NZ (1) | NZ186075A (en) |
SE (1) | SE7714659L (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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DE3005722A1 (en) * | 1980-02-15 | 1981-08-20 | Bayer Ag, 5090 Leverkusen | TRIFLUORMETHYLBENE CYL ESTER, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF IN PEST CONTROL |
CA1157884A (en) * | 1980-04-16 | 1983-11-29 | Byron R. Cotter | Process for the preparation of trifluoromethylbenzoyl halides |
-
1977
- 1977-12-21 NO NO774402A patent/NO774402L/en unknown
- 1977-12-22 AU AU31921/77A patent/AU3192177A/en active Pending
- 1977-12-22 DE DE19772757406 patent/DE2757406A1/en not_active Withdrawn
- 1977-12-22 NZ NZ186075A patent/NZ186075A/en unknown
- 1977-12-22 IL IL53680A patent/IL53680A0/en unknown
- 1977-12-22 DK DK575877A patent/DK575877A/en unknown
- 1977-12-22 GB GB53570/77A patent/GB1556566A/en not_active Expired
- 1977-12-22 FI FI773911A patent/FI773911A/en not_active Application Discontinuation
- 1977-12-22 SE SE7714659A patent/SE7714659L/en unknown
- 1977-12-23 NL NL7714301A patent/NL7714301A/en not_active Application Discontinuation
- 1977-12-23 JP JP15630677A patent/JPS5382771A/en active Pending
- 1977-12-23 ES ES465366A patent/ES465366A2/en not_active Expired
- 1977-12-23 LU LU78773A patent/LU78773A1/en unknown
- 1977-12-27 GR GR55032A patent/GR66082B/el unknown
Also Published As
Publication number | Publication date |
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GB1556566A (en) | 1979-11-28 |
NZ186075A (en) | 1979-11-01 |
JPS5382771A (en) | 1978-07-21 |
DE2757406A1 (en) | 1978-06-29 |
SE7714659L (en) | 1978-06-25 |
LU78773A1 (en) | 1979-07-20 |
AU3192177A (en) | 1979-06-28 |
DK575877A (en) | 1978-06-25 |
GR66082B (en) | 1981-01-15 |
ES465366A2 (en) | 1978-09-16 |
IL53680A0 (en) | 1978-03-10 |
NL7714301A (en) | 1978-06-27 |
FI773911A (en) | 1978-06-25 |
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