NO136714B - - Google Patents
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- Publication number
- NO136714B NO136714B NO3470/72A NO347072A NO136714B NO 136714 B NO136714 B NO 136714B NO 3470/72 A NO3470/72 A NO 3470/72A NO 347072 A NO347072 A NO 347072A NO 136714 B NO136714 B NO 136714B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- group
- carbon atoms
- solution
- alkyl
- Prior art date
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- 239000002253 acid Substances 0.000 claims description 68
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 22
- -1 alkaloid esters Chemical class 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 claims description 13
- 229960002726 vincamine Drugs 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- OZDNDGXASTWERN-CTNGQTDRSA-N Apovincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OC)N5C2=C1 OZDNDGXASTWERN-CTNGQTDRSA-N 0.000 claims description 6
- 150000001350 alkyl halides Chemical class 0.000 claims description 6
- 229950006936 apovincamine Drugs 0.000 claims description 6
- OZDNDGXASTWERN-UHFFFAOYSA-N apovincamine Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)C=C(C(=O)OC)N5C2=C1 OZDNDGXASTWERN-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229930013930 alkaloid Natural products 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- VLFDXKBCNKXRBE-YTQUADARSA-N (+)-Isoeburnamine Natural products O[C@@H]1n2c3c(c4c2[C@H]2[C@@](CC)(C1)CCC[N+]2CC4)cccc3 VLFDXKBCNKXRBE-YTQUADARSA-N 0.000 claims description 4
- HONLKDDLTAZVQV-NZSAHSFTSA-N Eburnamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@H]3[C@@]4(CC)C[C@@H](O)N5C2=C1 HONLKDDLTAZVQV-NZSAHSFTSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- HONLKDDLTAZVQV-UHFFFAOYSA-N eburnamine Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)N5C2=C1 HONLKDDLTAZVQV-UHFFFAOYSA-N 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims 2
- 239000000243 solution Substances 0.000 description 66
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 150000002148 esters Chemical class 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 239000000203 mixture Substances 0.000 description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 19
- 125000004494 ethyl ester group Chemical group 0.000 description 19
- 235000011121 sodium hydroxide Nutrition 0.000 description 19
- 238000004587 chromatography analysis Methods 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 230000002490 cerebral effect Effects 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 7
- 238000002329 infrared spectrum Methods 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000012670 alkaline solution Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 229940095064 tartrate Drugs 0.000 description 5
- 230000000304 vasodilatating effect Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 230000036284 oxygen consumption Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- LFQULJPVXNYWAG-UHFFFAOYSA-N sodium;phenylmethanolate Chemical compound [Na]OCC1=CC=CC=C1 LFQULJPVXNYWAG-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000002027 dichloromethane extract Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av terapeutisk aktive alkaloidestere og salter derav av eburnamintypen. The present invention relates to an analogous method for the production of therapeutically active alkaloid esters and salts thereof of the eburnamine type.
De nye forbindelser som fremstilles ifolge oppfinnelsen, har den generelle formel: The new compounds produced according to the invention have the general formula:
hvor</>X^Y er en gruppe eller where</>X^Y is a group or
R er en usubstituert alkoxycarbonylgruppe med 2-6 carbonatomer i alkylgruppen, en alkoxycarbonylgruppe inneholdende 1-6 carbonatomer i alkylgruppen substituert med en hydroxygruppe eller med et halogenatom, en alkenyloxycarbonylgruppe med 1-6 carbonatomer i alkenylgruppen eller en benzyloxycarbonylgruppe, eller salter eller kvartære derivater derav. R is an unsubstituted alkoxycarbonyl group with 2-6 carbon atoms in the alkyl group, an alkoxycarbonyl group containing 1-6 carbon atoms in the alkyl group substituted with a hydroxy group or with a halogen atom, an alkenyloxycarbonyl group with 1-6 carbon atoms in the alkenyl group or a benzyloxycarbonyl group, or salts or quaternary derivatives thereof .
Der er noen kjente derivater av vincamin og noen forbindelser som er beslektet med vincamin, som har farmakologiske aktiviteter analoge med dem for vincamin (f.eks. ungarsk patent 151,255 og 157.687). There are some known derivatives of vincamine and some compounds related to vincamine, which have pharmacological activities analogous to those of vincamine (eg Hungarian Patent 151,255 and 157,687).
Det har nu vist seg at nye alkaloidestere av eburnamintypen med den generelle formel (I) og deres salter har en betraktelig hoycre cerebral vasodilatorisk virkning enn vincamin. It has now been shown that new alkaloid esters of the eburnamine type with the general formula (I) and their salts have a considerably higher cerebral vasodilatory effect than vincamine.
Blant forbindelsene som fremstilles ifolge oppfinnelsen har de folgende betraktelig cerebral vasodilatorisk aktivitet: Among the compounds produced according to the invention, the following have considerable cerebral vasodilatory activity:
vincaminsyre-ethylester, vincamic acid ethyl ester,
vincaminsyre-allylester, vincamic acid allyl ester,
vincaminsyre-oxyethylester, vincamic acid oxyethyl ester,
vincaminsyre-klorethylester, vincamic acid chloroethyl ester,
vincaminsyre-benzylester, vincamic acid benzyl ester,
(+)-apovincaminsyre-ethylester, (+)-Apovicamic acid ethyl ester,
apovincaminsyre-butylester, apovincamic acid butyl ester,
eddiksyre-apovincaminolester, acetic acid apovincamino ester,
(-)-apovincaminsyre-ethylester, (-)-Apovicamic acid ethyl ester,
(+)-apovincaminsyre-ethylester-methojodid. (+)-Apovicamic acid ethyl ester methoiodide.
Blant de ovenfor anforte forbindelser er (+)-apovincaminsyre-ethylester, (-)-apovincaminsyre-ethylester og (+)-apovincaminsyre-ethylester-methojodid de mest foretrukne. Among the above compounds, (+)-apovincinamic acid ethyl ester, (-)-apovincinamic acid ethyl ester and (+)-apovincinamic acid ethyl ester methoiodide are the most preferred.
Resultatene av de farmakologiske forsok utfort med ovenstående forbindelser er oppfort i Tabell 1 og 2, sammen med de tilsvarende data for vincamin. Undersokelsene ble utfort på narkotiserte hunder. The results of the pharmacological experiments carried out with the above compounds are listed in Tables 1 and 2, together with the corresponding data for vincamine. The investigations were carried out on anesthetized dogs.
Arterieblodtrykket ble målt i venstre arteria femoralis med et elektromanometer. Hjertefrekvensen ble bestemt på grunnlag av den pulserende komponent av blodtrykket. Antallet av respirasjoner ble nålt sed en pneumotachograf. Den aortiske strom (volum pr. minutt) og den cerebrale strom (arteria carotis internal og arteria verte-bral strom på begge sider) ble målt med elektromagnetiske flow-metere anbragt på de respektive deler av kroppen. Oxygentrykket i det arteriske blod ble målt i arteria feraoralis, mens det for det cerebrale venose blod ble målt i sinns transversus. Sirkulasjons-motstanden av hele kroppen og av det cerebrale vasculære system, det cerebrale.oxygenforbruk og oxygenutnyttelse, såvel som utgangstrykket fra hjertet (hjerte-effektivitet) ble beregnet på basis av de ovenstående parametere som ble målt kontinuerlig. Arterial blood pressure was measured in the left femoral artery with an electromanometer. Heart rate was determined on the basis of the pulsatile component of blood pressure. The number of respirations was recorded using a pneumotachograph. The aortic stroma (volume per minute) and the cerebral stroma (arteria carotis internal and arteria vertebral stroma on both sides) were measured with electromagnetic flow meters placed on the respective parts of the body. The oxygen pressure in the arterial blood was measured in the feraoral artery, while that of the cerebral venous blood was measured in the transversus of the brain. The circulatory resistance of the whole body and of the cerebral vascular system, the cerebral oxygen consumption and oxygen utilization, as well as the output pressure from the heart (cardiac efficiency) were calculated on the basis of the above parameters which were measured continuously.
Ved sammenligning av virkningene av forbindelsene som ble undersokt, med de for vincamin viser det seg at de nye forbindelser har mere fordelaktige virkninger enn vincamin. De folgende fordeler kan nevnes: 1) De nye forbindelser har en kraftigere generell vasodilaterende virkning enn vincamin (bestemt på basis av den vasculære motstand i hele kroppen). 2) De har mindre markert blodtrykksenkende virkning enn vincamin (bestemt på basis av det midlere arterielle trykk). 3) Deres cerebrale vasodilaterende aktivitet overstiger den for vincamin (bestemt på basis av den cerebrale vasculære motstand). When comparing the effects of the compounds investigated with those of vincamine, it appears that the new compounds have more beneficial effects than vincamine. The following advantages can be mentioned: 1) The new compounds have a more powerful general vasodilatory effect than vincamine (determined on the basis of the vascular resistance in the whole body). 2) They have a less marked blood pressure-lowering effect than vincamine (determined on the basis of mean arterial pressure). 3) Their cerebral vasodilatory activity exceeds that of vincamine (determined on the basis of the cerebral vascular resistance).
h) Den cerebrale vasculære strom oker i storre grad. h) The cerebral vascular stroma increases to a greater extent.
5) Utgangstrykket fra hjertet (hjerte-effektivitet) avtar. 5) The output pressure from the heart (cardiac efficiency) decreases.
6) Hjertefrekvensen avtar ikke, men oker. 6) The heart rate does not decrease, but increases.
7) Mengden av blod som sendes ut av hjertet pr. minutt (volum pr. minutt) avtar ikke, men oker. 8) Det cerebrale oxygenforbruk oker i storre grad, folgelig utover de nye forbindelser en kraftigere innflytelse på stoffskiftet i de cerebrale vev enn vincamin (se de data som angår det cerebrale oxygenforbruk). 7) The amount of blood sent out of the heart per minute (volume per minute) does not decrease, but increases. 8) Cerebral oxygen consumption increases to a greater extent, consequently beyond the new compounds a stronger influence on the metabolism in the cerebral tissues than vincamine (see the data concerning cerebral oxygen consumption).
På basis av det ovenstående kan man slutte at foruten sin sterke vasodilaterende aktivitet har de nye forbindelser også en fordelaktig innflytelse på hjertefunksjonen, og de stimulerer stoffskiftet i de cerebrale vev ved å oke den cerebrale blodtllforsel. On the basis of the above, it can be concluded that in addition to their strong vasodilatory activity, the new compounds also have a beneficial influence on cardiac function, and they stimulate the metabolism in the cerebral tissues by increasing cerebral blood flow.
De nye alkaloidesterderivater med formel (I) med farmakologiske virkninger, fremstilles i henhold til oppfinnelsen ved at: a) et salt av apovincaminsyre eller av vincaminsyre omsettes med et alkylhalogenid med 2-6 carbonatomer, et alkylhalogenid med 1-6 carbonatomer substituert med et halogenatom eller en hydroxygruppe, et alkenylhalogenid med 1-6 carbomatoner, benzylhalogenid eller med de tilsvarende sulfater, eller b) apovincaminsyre eller vincaminsyre forestres med en alkohol med den generelle formel R-^-OH, hvor R-^ er en alkylgruppe med 2-6 carbonatomer, en alkylgruppe med 1-6 carbonatomer substituert med et halogenatom eller en hydroxygruppe, en alkenyl-gruppe med 1-6 carbonatomer eller en benzylgruppe, i nærvær av én eller flere katalysatorer, fortrinnsvis i nærvær av' mineral- eller organiske syrer eller alifatiske eller aromatiske sulfonsyrer, eller c) apovincamin eller vincamin omsettes med et alkalimetall-alkoholat, avledet av en alkohol med den generelle formel R2-OH hvor R2 er en alkylgruppe med 2-6 carbonatomer eller benzyl, eller d) apovincamin omsettes med en alkylester med 2-6 carbonatomer i alkylgruppen av en alifatisk carboxylsyre med 1-6 carbonatomer , The new alkaloid ester derivatives with formula (I) with pharmacological effects are prepared according to the invention by: a) a salt of apovincamic acid or of vincamic acid is reacted with an alkyl halide with 2-6 carbon atoms, an alkyl halide with 1-6 carbon atoms substituted with a halogen atom or a hydroxy group, an alkenyl halide with 1-6 carbomatones, benzyl halide or with the corresponding sulfates, or b) apovincamic acid or vincamic acid is esterified with an alcohol of the general formula R-^-OH, where R-^ is an alkyl group with 2-6 carbon atoms, an alkyl group of 1-6 carbon atoms substituted by a halogen atom or a hydroxy group, an alkenyl group of 1-6 carbon atoms or a benzyl group, in the presence of one or more catalysts, preferably in the presence of mineral or organic acids or aliphatic or aromatic sulphonic acids, or c) apovincamine or vincamine is reacted with an alkali metal alcoholate, derived from an alcohol of the general formula R2-OH where R2 is an alkyl group with 2-6 carbon atoms or benzyl, or d) apovincamine is reacted with an alkyl ester with 2-6 carbon atoms in the alkyl group of an aliphatic carboxylic acid with 1-6 carbon atoms,
og( om onskes, overfores de således erholdte nye alkaloidestere av eburnamintypen med den generelle formel (I) til deres syre-addisjonssalter eller kvartære salter ved å omsette dem med en mineralsyre eller organisk syre (f.eks. med saltsyre, hydrogenbromid, svovelsyre, fosforsyre, eddiksyre, sitronsyre, maleinsyre, vinsyre eller malinsyre) eller med et alkylhalogenid, og til slutt overfores eventuelt de således erholdte salter til de frie baser og/eller de frie baser overfores eventuelt til andre salter derav. and (if desired, the thus obtained new alkaloid esters of the eburnamine type of the general formula (I) are converted into their acid addition salts or quaternary salts by reacting them with a mineral acid or organic acid (e.g. with hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, tartaric acid or malic acid) or with an alkyl halide, and finally the salts thus obtained are optionally transferred to the free bases and/or the free bases are optionally transferred to other salts thereof.
Variant a) av fremgangsmåten ifolge oppfinnelsen utfores fortrinnsvis som folger: Hvis reagenset er et alkyl-, alkenyl-, substituert alkyl- eller benzylhalogenid, anvendes vannfri alkohol eller et overskudd av det passende halogenid som reaksjonsmedium. Hvis forestringen utfores med et alkylsulfat, kan reaksjonen utfores i en vannfri alkohol eller ether, i aceton, eller også i vannfri tetrahydrofuran. I hvert av disse tilfellene' utfores forestringen ved å koke reaksjonsblandingen under tilbakelop i flere timer. Adskillelsen av den krystallinske ester utfores ved fasebytterensning som folger: reaksjonsblandingen inndampes under nedsatt trykk, konsentratet fortynnes med en vandig opplosning av en syre, den sure vandige blanding gjores alkalisk, produktet ekstraheres i et organisk opplosningsmiddel, den organiske opplosning inndampes og residuet omkrystalliseres. Ved denne fremgangsmåte fåes krystallinske forbindelser med formel (I). Variant a) of the method according to the invention is preferably carried out as follows: If the reagent is an alkyl, alkenyl, substituted alkyl or benzyl halide, anhydrous alcohol or an excess of the appropriate halide is used as reaction medium. If the esterification is carried out with an alkyl sulphate, the reaction can be carried out in an anhydrous alcohol or ether, in acetone, or also in anhydrous tetrahydrofuran. In each of these cases, the esterification is carried out by boiling the reaction mixture under reflux for several hours. The separation of the crystalline ester is carried out by phase change purification as follows: the reaction mixture is evaporated under reduced pressure, the concentrate is diluted with an aqueous solution of an acid, the acidic aqueous mixture is made alkaline, the product is extracted in an organic solvent, the organic solution is evaporated and the residue is recrystallized. By this method, crystalline compounds of formula (I) are obtained.
Variant b) av foreliggende fremgangsmåte utfores fortrinnsvis Variant b) of the present method is preferably carried out
i nærvær av et opplosningsmiddel. Som opplosningsmidler kan anvendes f.eks. et overskudd av den passende alkohol, og/eller vannfri benzen eller toluen. Den in the presence of a solvent. Solvents can be used, e.g. an excess of the appropriate alcohol, and/or anhydrous benzene or toluene. It
sure katalysator kan være ethansulfonsyre. Reaksjonen utfores ved å koke blandingen under tilbakelop i flere timer. Den erholdte ester fraskilles og renses ved fasebytte. acid catalyst may be ethanesulfonic acid. The reaction is carried out by boiling the mixture under reflux for several hours. The ester obtained is separated and purified by phase change.
Variant c) av foreliggende fremgangsmåte utfores fortrinnsvis Variant c) of the present method is preferably carried out
i et apolart opplosningsmiddel eller opplosningsmiddelblanding (helst i benzen). Reaksjonsblandingen inneholdende et alkalimetall-alkoholat, fortrinnsvis natriumalkoholat, kokes under tilbakelop i flere timer, derefter fraskilles det erholdte produkt og renses ved fasebytte. in an apolar solvent or solvent mixture (preferably in benzene). The reaction mixture containing an alkali metal alcoholate, preferably sodium alcoholate, is refluxed for several hours, then the product obtained is separated and purified by phase change.
Variant d) av foreliggende fremgangsmåte utfores fortrinnsvis Variant d) of the present method is preferably carried out
i nærvær av et opplosningsmiddel eller opplosningsmiddelblanding, spesielt i nærvær av en alkohol og/eller i nærvær av storre mengder av den passende esterreaktant. Reaksjonen utfores som beskrevet under variant c). in the presence of a solvent or solvent mixture, especially in the presence of an alcohol and/or in the presence of large amounts of the appropriate ester reactant. The reaction is carried out as described under variant c).
De nye fremgangsmåteforbindelser kan anvendes i terapien The new process compounds can be used in therapy
i form av farmasøytiske preparater. Disse farmasøytiske preparater kan inneholde forskjellige organiske eller mineralske bærere egnet for enteral eller parenteral administrasjon, som ikke inngår noen reaksjon med de nye esterderivater. in the form of pharmaceutical preparations. These pharmaceutical preparations may contain various organic or mineral carriers suitable for enteral or parenteral administration, which do not enter into any reaction with the new ester derivatives.
De farmasøytiske produkter kan inneholde de nye forbindelser alene eller sammen med andre kjente aktive midler, f.eks. i kombina-sjon med reserpin. The pharmaceutical products may contain the new compounds alone or together with other known active agents, e.g. in combination with reserpine.
De farmasøytiske produkter kan være sterile om onskes. Prepa-ratene kan også inneholde andre hjelpestoffer, f.eks. salter for å innstille det osmotiske trykk til den onskede verdi, puffere, etc. The pharmaceutical products can be sterile if desired. The preparations may also contain other excipients, e.g. salts to adjust the osmotic pressure to the desired value, buffers, etc.
Oppfinnelsen vil bli illustrert ved hjelp av de folgende eks-empler. The invention will be illustrated by means of the following examples.
Eksempel 1 Example 1
Vincaminsyre- ethylester Vincamic acid ethyl ester
1 g (0,0029 mol) vincaminsyre og 0,11 g (0,0027 mol) natriumhydroxyd opploses i 50 ml vannfri ethanol. 0,35 g (0,0029 mol) ethylbromid tilsettes til oppløsningen og reaksjonsblandingen kokes under tilbakelop i 2 timer. I lopet av denne tid begynner krystall-insk stoff å utskilles fra oppløsningen. De dannede krystaller opp-løses ved tilsetning av 0,01 g natriumhydroxyd. Derefter tilsettes en ytterligere mengde på 0,10 g ethylbromid til oppløsningen, og reaksjonsblandingen kokes under tilbakelop i ytterligere 2 timer. Oppløsningen avkjøles og inndampes til torrhet under nedsatt trykk. Det torre residuum opploses i 300 ml methylenklorid og denne opplosning ekstraheres med 100 ml 5%-ig vandig natriumhydroxydopplbsning for å fjerne den uomsatte vincaminsyre og natriumklorid dannet ved reaksjonen. Den organiske fase fraskilles og tørres over vannfritt kaliumcarbonat. Blandingen filtreres og filtratet inndampes til torrhet under nedsatt trykk. Det torre residuum opploses i 20 ml methanol og oppløsningen hensettes ved 0-2°C i ca. 10 timer. Det utskilte krystallinske produkt renses ved omkrystallisasjon fra vannfri ethanol. 1 g (0.0029 mol) of vincamic acid and 0.11 g (0.0027 mol) of sodium hydroxide are dissolved in 50 ml of anhydrous ethanol. 0.35 g (0.0029 mol) ethyl bromide is added to the solution and the reaction mixture is refluxed for 2 hours. During this time, crystalline material begins to separate from the solution. The formed crystals are dissolved by adding 0.01 g of sodium hydroxide. A further amount of 0.10 g of ethyl bromide is then added to the solution and the reaction mixture is refluxed for a further 2 hours. The solution is cooled and evaporated to dryness under reduced pressure. The dry residue is dissolved in 300 ml of methylene chloride and this solution is extracted with 100 ml of 5% aqueous sodium hydroxide solution to remove the unreacted vincamic acid and sodium chloride formed by the reaction. The organic phase is separated and dried over anhydrous potassium carbonate. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The dry residue is dissolved in 20 ml of methanol and the solution is kept at 0-2°C for approx. 10 hours. The separated crystalline product is purified by recrystallization from anhydrous ethanol.
0,82 g (82%) av vincaminsyre-ethylester fåes. Produktet er ensartet på grunnlag av skiktkromatografi. Sm.p.: 2hh°C (Boetius). 0.82 g (82%) of vincamic acid ethyl ester is obtained. The product is uniform on the basis of layer chromatography. Melting point: 2hh°C (Boetius).
[oc]p° = +63,6° (c = 1, i pyridin). [oc]p° = +63.6° (c = 1, in pyridine).
Elementæranalyse: Elemental analysis:
Beregnet: C = 71,71$ H = 7,66$ N = 7,60$ Calculated: C = $71.71 H = $7.66 N = $7.60
Funnet: C = 72,03$ H = '8,28$ N = 7 , k?% Found: C = 72.03$ H = '8.28$ N = 7 , k?%
Strukturen av produktet identifiseres ved dets IR-spektrum (et esterbånd vises ved 5,71 U>). The structure of the product is identified by its IR spectrum (an ester band appears at 5.71 U>).
Eksempel 2 Example 2
Vincaminsyre- allylester Vincamic acid allyl ester
1 g (0,0029 mol) vincaminsyre og 0,11 g (0,0027 mol) natriumhydroxyd opploses i 120 ml vannfri ethanol. 0,5 g (0,00^1 mol) allylbromid tilsettes til opplosningen og reaksjonsblandingen kokes under tilbakelop i 1 time. Dannelsen av vincaminsyre-allylester folges ved skiktkromatografi. Når flekken for vincaminsyre forsvinner, stanses kokingen. Opplosningen avkjoles og inndampes til torrhet. 1 g (0.0029 mol) of vincamic acid and 0.11 g (0.0027 mol) of sodium hydroxide are dissolved in 120 ml of anhydrous ethanol. 0.5 g (0.00^1 mol) of allyl bromide is added to the solution and the reaction mixture is refluxed for 1 hour. The formation of vincamic acid allyl ester is followed by layer chromatography. When the stain for vincamic acid disappears, the boiling is stopped. The solution is cooled and evaporated to dryness.
Det torre residuum opploses i 200 ml 2$-ig vandig svovelsyre og opplosningen ekstraheres med 2 x 200 ml benzen. Den fraskilte vannfases pH innstilles på 8 med 5$-ig vandig ammoniakk, derefter ekstraheres den svakt alkaliske opplosning med 5 x 200 ml benzen. Den erholdte organiske opplosning torres over vannfritt kaliumcarbonat, filtreres og inndampes til torrhet. Det torre residuum opploses i 10 ml vannfri ethanol, og denne opplosning hensettes ved 0-2°C i ca. 10 timer. De utskilte krystaller frafiltreres og omkrystalliseres fra vannfri ethanol. The dry residue is dissolved in 200 ml of 2% aqueous sulfuric acid and the solution is extracted with 2 x 200 ml of benzene. The pH of the separated water phase is adjusted to 8 with 5 µg of aqueous ammonia, then the slightly alkaline solution is extracted with 5 x 200 ml of benzene. The organic solution obtained is dried over anhydrous potassium carbonate, filtered and evaporated to dryness. The dry residue is dissolved in 10 ml of anhydrous ethanol, and this solution is kept at 0-2°C for approx. 10 hours. The separated crystals are filtered off and recrystallized from anhydrous ethanol.
0,8'+ g av vincaminsyre-allylesteren fåes (utbytte: 8<1>+$). På basis av skiktkromatografi fåes et ensartet produkt. Sm.p.: 236°C (Boetius). 0.8'+ g of the vincamic acid allyl ester is obtained (yield: 8<1>+$). On the basis of layer chromatography, a uniform product is obtained. Melting point: 236°C (Boetius).
Elementæranalyse: Elemental analysis:
Beregnet: C = 72,60$ H = 7,<1>+1$ N = 7,39$ Calculated: C = 72.60$ H = 7.<1>+1$ N = 7.39$
Funnet: C = 72,V8$ H - 7,^0$ N = 7 Found: C = 72.V8$ H - 7.^0$ N = 7
Produktets struktur identifiseres ved dets IR-spektrum (et esterbånd vises ved 5,72^-). The structure of the product is identified by its IR spectrum (an ester band appears at 5.72^-).
Eksempel 3 Example 3
Vincaminsyre- oxyethylester Vincamic acid oxyethyl ester
1 g (0,0029 mol) vincaminsyre og 0,11 g (0,0027 mol) natriumhydroxyd suspenderes i 10 ml ethylenklorhydrin, derefter opploses de faste stoffer i reaksjonsmediet ved oppvarmning. Opplosningen kokes under tilbakelop i 3 timer. Dannelsen av esteren folges ved skikt-kromatograf i. Når flekken som er karakteristisk for vincaminsyre forsvinner, stanses kokingen. Opplosningen avkjoles og 500 ml 2%- ig vandig svovelsyre tilsettes. Den sure oppløsnings pH innstilles på 8 ved tilsetning av en 5$-ig vandig natriumhydroxydopplosning. Et bunnfall utskilles. Blandingen ekstraheres med 5 x 200 ml benzen. Den organiske opplosning fraskilles, torres over vannfritt kaliumcarbonat og filtreres. Benzenopplosningen inndampes til torrhet, og residuet krystalliseres fra 10 ml ether. Den etheriske opplosning hensettes i 10 timer, derefter frafiltreres de utskilte krystaller og omkrystalliseres fra vannfri methanol. 1 g (0.0029 mol) of vincamic acid and 0.11 g (0.0027 mol) of sodium hydroxide are suspended in 10 ml of ethylene chlorohydrin, then the solids are dissolved in the reaction medium by heating. The solution is boiled under reflux for 3 hours. The formation of the ester is followed by layer chromatography. When the stain characteristic of vincamic acid disappears, the boiling is stopped. The solution is cooled and 500 ml of 2% aqueous sulfuric acid is added. The pH of the acidic solution is adjusted to 8 by adding a 5% aqueous sodium hydroxide solution. A precipitate is separated. The mixture is extracted with 5 x 200 ml of benzene. The organic solution is separated, dried over anhydrous potassium carbonate and filtered. The benzene solution is evaporated to dryness, and the residue is crystallized from 10 ml of ether. The ethereal solution is allowed to stand for 10 hours, then the precipitated crystals are filtered off and recrystallized from anhydrous methanol.
0,72 g ( 72%) vincaminsyre-oxyethylester fåes. På basis av skiktkromatografi dannes et ensartet produkt. Smeltepunkt: 171°C (Boetius). 0.72 g (72%) of vincamic acid oxyethyl ester is obtained. On the basis of layer chromatography, a uniform product is formed. Melting point: 171°C (Boetius).
Elementæranalyse: Elemental analysis:
Beregnet: C = 68,66$ H = 7,36$ N = 7,32$ Calculated: C = $68.66 H = $7.36 N = $7.32
Funnet: 0 = 69,28$ H - 7,86$ N "-- 7,58$ Found: 0 = $69.28 H - $7.86 N "-- $7.58
Produktets struktur identifiseres ved dets IR-spektraa (et esterbåd vises ved 5,79-/U-). The structure of the product is identified by its IR spectra (an ester boat appears at 5.79-/U-).
Eksempel h Example h
Vlncaminsyre- klorethylester Vlcamic acid- chloroethyl ester
1 g (0,0029 mol) vincaminsyre og 0,11 g (0,0027 mol) natriumhydroxyd opploses i 80 ml vannfri'ethanol. Opplosningen inndampes til torrhet under nedsatt trykk. Det torre residuum opploses i h0 ml vannfri acetonitril, og 20 ml 1,2-diklorethan tilsettes til opplosningen. Den erholdte blanding kokes under tilbakelop i h timer. Dannelsen av esteren folges ved skiktkromatografi. Når flekken som er karakteristisk for vincaminsyre, forsvinner, stanses kokingen. Opplosningen inndampes til torrhet under nedsatt trykk, 1 g (0.0029 mol) of vincamic acid and 0.11 g (0.0027 mol) of sodium hydroxide are dissolved in 80 ml of anhydrous ethanol. The solution is evaporated to dryness under reduced pressure. The dry residue is dissolved in 10 ml of anhydrous acetonitrile, and 20 ml of 1,2-dichloroethane is added to the solution. The resulting mixture is boiled under reflux for h hours. The formation of the ester is followed by layer chromatography. When the stain characteristic of vincamic acid disappears, the boiling is stopped. The solution is evaporated to dryness under reduced pressure,
og det torre residuum opploses i 200 ml 2$-ig vandig svovelsyre. Den sure opplosnings pH innstilles på 8 med en 5$-ig vandig natriumhydroxydopplosning. Et bunnfall utskilles. Blandingen ekstraheres med 5 x 200 ml benzen, og den organiske fase torres over vannfritt kaliumcarbonat. Benzenopplosningen filtreres, og filtratet inndampes til torrhet under nedsatt .trykk. Det torre residuum krystalliseres fra 10 ml ether, og de erholdte krystaller omkrystalliseres fra and the dry residue is dissolved in 200 ml of 2% aqueous sulfuric acid. The pH of the acidic solution is adjusted to 8 with a 5% aqueous sodium hydroxide solution. A precipitate is separated. The mixture is extracted with 5 x 200 ml of benzene, and the organic phase is dried over anhydrous potassium carbonate. The benzene solution is filtered, and the filtrate is evaporated to dryness under reduced pressure. The dry residue is crystallized from 10 ml of ether, and the crystals obtained are recrystallized from
vannfri methanol. anhydrous methanol.
0,68 g (68$) vincaminsyre-klorethylester fåes. På basis av skiktkromatografi dannes et ensartet produkt. Sm.p.: 2l8°C (Boetius). 0.68 g ($68) of vincamic acid chloroethyl ester is obtained. On the basis of layer chromatography, a uniform product is formed. Melting point: 2l8°C (Boetius).
Elementæranalyse: Elemental analysis:
Beregnet: C = 65,58$ H = 6,75$ N = 6,95$ Calculated: C = $65.58 H = $6.75 N = $6.95
Funnet: C = 65,21$ H = 6,52$ N = 6,89$ Found: C = $65.21 H = $6.52 N = $6.89
Strukturen av forbindelsen identifiseres på basis av.dens IR-spektrum (et esterbånd vises ved 5,72 AO. The structure of the compound is identified on the basis of its IR spectrum (an ester band appears at 5.72 AO.
Eksempel 5 Example 5
Vincaminsyre- benzylester- tartrat Vincamic acid benzyl ester tartrate
1 g (0,0028 mol) vincamin opploses i 125 ml vannfri benzen, og 1 g (0.0028 mol) of vincamine is dissolved in 125 ml of anhydrous benzene, and
3 ml natriumbenzylatopplosning tilsettes til den ovenstående opplosning.<;>(Opplosningen av natriumbenzylat fremstilles fra 10 ml benzyl-alkohol og 0,2 g metallisk natrium på kjent vis). Opplosningen kokes under tilbakelop i 2 timer. Reaksjonen folges ved skiktkromatografi. Hvis den kromatografiske analyse viser en ufullstendig reaksjon, tilsettes ytterligere 1 ml natriumbenzylatopplosning til blandingen, og blandingen kokes i ytterligere .1 time. Når reaksjonen er fullstendig, tilsettes 300 ml benzen til opplosningen, og blandingen ekstraheres med 200 ml porsjoner 2$-lg vandig svovelsyre inntil den sure fase ikke viser en positiv Mayer-reaksjon.• Vannfasen fraskilles. Vann-fasens pH innstilles på 8 med 5$-ig vandig natriumhydroxydopplosning, og den alkaliske opplosning ekstraheres med 5 x 20 ml diklormethan. De organiske oppløsninger forenes og torres over vannfritt kaliumcarbonat. Opplosningen filtreres og inndampes til torrhet. Det torre residuum opploses i 15 ml ether, og en mettet etherisk opplosning av vinsyre tilsettes i en mengde tilstrekkelig til å innstille blandingens pH på 3» Opplosningen får lov til å krystallisere i ca. 10 timer. Det hvite, krystallinske vincaminsyre-benzylester-tartrat frafiltreres og omkrystalliseres fra aceton. 0,7^ g (7<*>+$) vincaminsyre-benzylester-tartrat fåes. På basis av skiktkromatografi dannes et ensartet produkt. Sm.p.: 115°C (Boetius). 3 ml of sodium benzylate solution is added to the above solution. (The solution of sodium benzylate is prepared from 10 ml of benzyl alcohol and 0.2 g of metallic sodium in a known manner). The solution is boiled under reflux for 2 hours. The reaction is followed by layer chromatography. If the chromatographic analysis shows an incomplete reaction, an additional 1 mL of sodium benzylate solution is added to the mixture, and the mixture is boiled for an additional .1 hour. When the reaction is complete, 300 ml of benzene is added to the solution, and the mixture is extracted with 200 ml portions of 2$-lg aqueous sulfuric acid until the acidic phase does not show a positive Mayer reaction. • The aqueous phase is separated. The pH of the water phase is adjusted to 8 with 5% aqueous sodium hydroxide solution, and the alkaline solution is extracted with 5 x 20 ml of dichloromethane. The organic solutions are combined and dried over anhydrous potassium carbonate. The solution is filtered and evaporated to dryness. The dry residue is dissolved in 15 ml of ether, and a saturated ethereal solution of tartaric acid is added in an amount sufficient to adjust the pH of the mixture to 3". The solution is allowed to crystallize for approx. 10 hours. The white, crystalline vincamic acid benzyl ester tartrate is filtered off and recrystallized from acetone. 0.7^ g (7<*>+$) of vincamic acid benzyl ester tartrate is obtained. On the basis of layer chromatography, a uniform product is formed. Melting point: 115°C (Boetius).
Elementæranalyse: Elemental analysis:
Beregnet: C = 6^,12$ H = 6,25$ N =<l>+,82$ Calculated: C = 6^.12$ H = 6.25$ N =<l>+.82$
Funnet: C = 63,98$ H = 6,33$ N = 5,02$ Found: C = $63.98 H = $6.33 N = $5.02
Strukturen av produktet identifiseres på basis av dets IR-spektrum (et esterbånd vises ved 5,75aO. The structure of the product is identified on the basis of its IR spectrum (an ester band appears at 5.75aO.
Eksempel 6 Example 6
Apovincaminsyre- ethylester Apovincamic acid ethyl ester
a) 1 g (0,0031 mol) apovincaminsyre og 0,17 g (0,003 mol) kaliumhydroxyd opploses i 80 ml vannfri ethanol, derefter tilsettes a) Dissolve 1 g (0.0031 mol) apovincamic acid and 0.17 g (0.003 mol) potassium hydroxide in 80 ml anhydrous ethanol, then add
0, k g (0,0036 mol) ethylbromid til opplosningen. Opplosningen kakes under tilbakelop i 3 timer. Reaksjonen folges ved skiktkromatografi. Opplosningen avkjbles og inndampes til torrhet under nedsatt trykk. Det torre residuum opploses i 500 ml 2%- ig vandig svovelsyre, og opplosningen filtreres. Filtratets pH innstilles på 8 med 5$-ig vandig natriumhydroxydopplosning. En liten mengde bunnfall utskilles. Blandingen ekstraheres med 200 ml porsjoner methylenklorid inntil ingen positiv Mayer-reaksjon kan iakttas i vannfasen. De organiske faser fraskilles, forenes, torres over vannfritt kaliumcarbonat, filtreres og inndampes til torrhet under nedsatt trykk. Det torre residuum opploses i 10 ml vannfri ethanol, og opplosningen hensettes til krystallisasjon ved 0-2°C i 10 timer. 0,66 g apovincaminsyre-ethylester fåes (utbytte: 66%). På basis av skiktkromatografi fåes et ensartet produkt. Smeltepunkt: 1<1>+<1>+°C (Boetius). 0.k g (0.0036 mol) of ethyl bromide to the solution. The solution is refluxed for 3 hours. The reaction is followed by layer chromatography. The solution is cooled and evaporated to dryness under reduced pressure. The dry residue is dissolved in 500 ml of 2% aqueous sulfuric acid, and the solution is filtered. The pH of the filtrate is adjusted to 8 with 5% aqueous sodium hydroxide solution. A small amount of precipitate is separated. The mixture is extracted with 200 ml portions of methylene chloride until no positive Mayer reaction can be observed in the water phase. The organic phases are separated, combined, dried over anhydrous potassium carbonate, filtered and evaporated to dryness under reduced pressure. The dry residue is dissolved in 10 ml of anhydrous ethanol, and the solution is allowed to crystallize at 0-2°C for 10 hours. 0.66 g of apovincamic acid ethyl ester is obtained (yield: 66%). On the basis of layer chromatography, a uniform product is obtained. Melting point: 1<1>+<1>+°C (Boetius).
Elementæranalyse: Elemental analysis:
Beregnet: C = 75,^0$ H = 7, h8% N = 7,99$ Calculated: C = 75.^0$ H = 7, h8% N = 7.99$
Funnet: C = 75,20$ H = 7,52$ N = 8,02$ Found: C = $75.20 H = $7.52 N = $8.02
Produktet identifiseres på basis av dets IR-spektrum (et esterbånd vises ved 5,75 A^). The product is identified on the basis of its IR spectrum (an ester band appears at 5.75 A^).
b) 1 g (0,0029 mol) vincaminsyre og 0,11 g (0,0027 mol) natriumhydroxyd opploses i 200 ml absolutt ethanol. Opplosningen opp-varmes under tilbakelop , og når kokning begynner, tilsettes 10 ml konsentrert ethansulfonsyre til opplosningen. Dannelsen av apovincaminsyre-ethylester folges ved skiktkromatografi. Efter 3 timers kokning konsentreres opplosningen til ca. 20 ml under nedsatt trykk. 500 ml destillert vann tilsettes til konsentratet, og blandingen anbringes i en skilletrakt. Oppløsningens pH innstilles på 8 med 5$-ig .vandig natriumhydroxydopplosning. Et bunnfall utskilles. Blandingen ekstraheres med 5 x 200 ml methylenklorid, og den organiske opplosning torres over vannfritt kaliumcarbonat. Opp- b) 1 g (0.0029 mol) of vincamic acid and 0.11 g (0.0027 mol) of sodium hydroxide are dissolved in 200 ml of absolute ethanol. The solution is heated under reflux, and when boiling begins, 10 ml of concentrated ethanesulfonic acid is added to the solution. The formation of apovincamic acid ethyl ester is followed by layer chromatography. After 3 hours of boiling, the solution is concentrated to approx. 20 ml under reduced pressure. 500 ml of distilled water is added to the concentrate, and the mixture is placed in a separatory funnel. The pH of the solution is adjusted to 8 with 5% aqueous sodium hydroxide solution. A precipitate is separated. The mixture is extracted with 5 x 200 ml of methylene chloride, and the organic solution is dried over anhydrous potassium carbonate. Up-
lbsningen filtreres og inndampes til torrhet under nedsatt trykk. the solution is filtered and evaporated to dryness under reduced pressure.
Det torre residuum opploses i 20 ml ethanol, og opplosningen hensettes til krystallisering ved 0 - 2°C. 0,86 g (86$) apovincaminsyre-ethylester fåes. På basis av skiktkromatografi-dannes et ensartet produkt. Sm.p.: lMt^C (Boetius). The dry residue is dissolved in 20 ml of ethanol, and the solution is allowed to crystallize at 0 - 2°C. 0.86 g ($86) of apovincamic acid ethyl ester is obtained. On the basis of layer chromatography, a uniform product is formed. Sm.p.: lMt^C (Boetius).
Eksempel 7 Example 7
Apovincaminsyre- butylester Apovincamic acid butyl ester
1 g (0,0031 mol) apovincaminsyre og 0,12 g (0,003 mol) natriumhydroxyd opploses i 80 ml vannfri ethanol, derefter tilsettes 0,5 g (0,003 mol) butylbromid til opplosningen. Opplosningen kokes under tilbakelop i h timer. Reaksjonen folges ved skiktkromatografi. Når reaksjonen er fullstendig, avkjoles opplosningen og inndampes til torrhet under nedsatt trykk. Det torre residuum opploses i 500 ml 2$-ig vandig svovelsyre, og den vandige opplosning's pH innstilles på 8 ved tilsetning av 5$-ig vandig natriumhydroxydopplosning. Den erholdte alkaliske opplosning ekstraheres med 5 x 200 ml benzen. Benzen-opplosningene forenes, torres over vannfritt kaliumcarbonat, filtreres og inndampes til torrhet under nedsatt trykk. Det torre residuum krystalliseres fra 10 ml ether. Det erholdte krystallinske stoff omkrystalliseres fra aceton. 1 g (0.0031 mol) of apovincamic acid and 0.12 g (0.003 mol) of sodium hydroxide are dissolved in 80 ml of anhydrous ethanol, then 0.5 g (0.003 mol) of butyl bromide is added to the solution. The solution is boiled under reflux for h hours. The reaction is followed by layer chromatography. When the reaction is complete, the solution is cooled and evaporated to dryness under reduced pressure. The dry residue is dissolved in 500 ml of 2% aqueous sulfuric acid, and the pH of the aqueous solution is adjusted to 8 by adding 5% aqueous sodium hydroxide solution. The alkaline solution obtained is extracted with 5 x 200 ml of benzene. The benzene solutions are combined, dried over anhydrous potassium carbonate, filtered and evaporated to dryness under reduced pressure. The dry residue is crystallized from 10 ml of ether. The crystalline substance obtained is recrystallized from acetone.
0,70 g (70$) apovincaminsyre-butylester fåes. På basis av skiktkromatografi dannes et ensartet produkt. Sm.p.: 175°C (spalt-ning) (Boetius). 0.70 g (70$) of apovincamic acid butyl ester is obtained. On the basis of layer chromatography, a uniform product is formed. Melting point: 175°C (decomposition) (Boetius).
Elementæranalyse: Elemental analysis:
Beregnet: C = 76,15$ H = 7,99$ N = 7A0$ Calculated: C = 76.15$ H = 7.99$ N = 7A0$
Funnet: C = 76,18$ H = 7,83$ N = 7,39$ Found: C = $76.18 H = $7.83 N = $7.39
Strukturen av produktet identifiseres på basis av dets IR-spektrum (et esterbånd vises ved 5,75/0. The structure of the product is identified on the basis of its IR spectrum (an ester band appears at 5.75/0.
Eksempel 8 Example 8
1,0 g (0,003 mol) apovincaminsyre tilsettes 20 ml ethanol 1.0 g (0.003 mol) of apovincamic acid is added to 20 ml of ethanol
og 3 dråper konsentrert svovelsyre. Blandingen kokes under til-bakeløp i 8 timer. Reaksjonens forløp kan følges ved tynnskiktskromatografi . Efter avsluttet reaksjon avkjøles rea ksjonsbland-ingen, og overskudd av ethanol avdestilleres under nedsatt trykk. Det erholdte oljeaktige residuum tilsettes 30 ml 2%-ig vandig svovelsyre, derpå innstilles pH på 8 med en oppløsning av 10%-ig vandig nat riumhydroxydoppløsning. Den alkaliske oppløsning ekstraheres med 3 x 30 ml diklormethan, det forenede diklormethanekstrakt tørres med vannfritt calciumcarbonat og inndampes til tørrhet under nedsatt trykk. Det erholdte 0,49tørre residuum renses gjennom en kromatografikolonne med tredobbelt mengde aluminiumoxyd (aktivitet III). Der elueres med benzen, og av eluatet oppsamles 5 ml fraksjoner. Den ønskede apovincaminsyre-ethylester fåes i fraksjon 1 og 2 som kombineres og inndampes til tørrhet under nedsatt trykk. Som residuum fåes 0,3 g apovincaminsyre-ethylester med smp. l44°c. and 3 drops of concentrated sulfuric acid. The mixture is boiled under reflux for 8 hours. The progress of the reaction can be followed by thin-layer chromatography. After completion of the reaction, the reaction mixture is cooled, and excess ethanol is distilled off under reduced pressure. The obtained oily residue is added to 30 ml of 2% aqueous sulfuric acid, then the pH is adjusted to 8 with a solution of 10% aqueous sodium hydroxide solution. The alkaline solution is extracted with 3 x 30 ml of dichloromethane, the combined dichloromethane extract is dried with anhydrous calcium carbonate and evaporated to dryness under reduced pressure. The 0.49 dry residue obtained is purified through a chromatography column with three times the amount of aluminum oxide (activity III). Elute with benzene, and 5 ml fractions of the eluate are collected. The desired apovincamic acid ethyl ester is obtained in fractions 1 and 2, which are combined and evaporated to dryness under reduced pressure. 0.3 g of apovincamic acid ethyl ester with mp. l44°c.
E ksempel 9 Example 9
0,25 g (0,00074 mol) apovincamin oppløses i 15 ml toluen, oppløsningen tilsettes 0,1 g (0,00089 mol) kalium-t-butylat, og blandingen kokes under tilbakeløp i 10 timer. Forløpet av reaksjonen kan følges ved tynnskiktskromatografi (adsorbent: aluminiumoxyd, elueringsmiddel: benzen-acetonitril 10:1). Efter avsluttet reaksjon tilsettes reaksjonsblandingen 20 ml vann og 20 ml benzen, omrøres i 2 minutter og hensettes så. Efter fase-adskillelse omrøres den organiske fase igjen med 20 ml vann, derpå skilles fasen igjen, den organiske fase tørres med kaliumcarbonat og inndampes så under nedsatt trykk til tørrhet. Residuet oppløses i 1 ml benzen og filtreres gjennom et 1 - 2 cm tykt lag av 5 g aluminiumoxyd (aktivitet III) og eftervaskes med 10 ml benzen. Den ønskede ester fåes i benzenoppløsningen som inndampes til tørrhet under nedsatt trykk. Man får 0,06 g apovincaminsyre-t-butylester (21% av det teoretiske), R 0,31. 0.25 g (0.00074 mol) of apovincamine is dissolved in 15 ml of toluene, 0.1 g (0.00089 mol) of potassium t-butylate is added to the solution, and the mixture is refluxed for 10 hours. The course of the reaction can be followed by thin-layer chromatography (adsorbent: aluminum oxide, eluent: benzene-acetonitrile 10:1). After completion of the reaction, 20 ml of water and 20 ml of benzene are added to the reaction mixture, stirred for 2 minutes and then set aside. After phase separation, the organic phase is stirred again with 20 ml of water, then the phase is separated again, the organic phase is dried with potassium carbonate and then evaporated under reduced pressure to dryness. The residue is dissolved in 1 ml of benzene and filtered through a 1 - 2 cm thick layer of 5 g of aluminum oxide (activity III) and washed with 10 ml of benzene. The desired ester is obtained in the benzene solution, which is evaporated to dryness under reduced pressure. 0.06 g of apovincamic acid t-butyl ester is obtained (21% of the theoretical), R 0.31.
Det på ovenstående måte erholdte oljeaktige produkt bringes til pH 4 ved tilsetning av en mettet oppløsning av citronsyre i diethylether. Citratsaltet begynner straks å falle ut. Blandingen hensettes i kjøleskap i 12 timer, derpå f raf Utreres det utskilte salt, vaskes med 8 - 10 ml avkjølt diethylether og tørres. Man får på denne måte 0,052 g apovincaminsyre-t-butylester-eitrat (12,04% av det teoretiske), smp. lOO - 108°C The oily product obtained in the above manner is brought to pH 4 by adding a saturated solution of citric acid in diethyl ether. The citrate salt immediately starts to fall out. The mixture is kept in a refrigerator for 12 hours, then the separated salt is filtered off, washed with 8 - 10 ml of cooled diethyl ether and dried. In this way, 0.052 g of apovincamic acid t-butyl ester eitrate (12.04% of the theoretical) is obtained, m.p. 100 - 108°C
[a]D= +6o,2° (c = 1, i pyridin). [a]D= +60.2° (c = 1, in pyridine).
Analyse for O^H^I^O^ Analysis for O^H^I^O^
Beregnet: C 63,1%, H 6,6%, N 4,9%; Calculated: C 63.1%, H 6.6%, N 4.9%;
Funnet: C 63,0%, H 6,5%, N 4,9%. Found: C 63.0%, H 6.5%, N 4.9%.
Eksempel 10 Example 10
2 ml n-butylalkohol tilsettes en katalytisk mengde natrium-metall. Efter oppløsning av metallet tilsettes 5 ml n-butyl-acetat og 0,2 g apovincamin. Blandingen kokes under tilbakeløp i 7 timer idet methylacetatet som dannes, kontinuerlig avdestilleres. 2 ml of n-butyl alcohol is added to a catalytic amount of sodium metal. After dissolving the metal, 5 ml of n-butyl acetate and 0.2 g of apovincamine are added. The mixture is boiled under reflux for 7 hours, while the methyl acetate that is formed is continuously distilled off.
Reaksjonens forløp følges ved tynnskiktskromatografi. Efter avsluttet reaksjon tilsettes reaks jonsblandingen 10 ml vann, og ekstraheres så med 3 x lo ml diklormethan. Diklormethanekstrakt ene forenes, tørres med vannfritt kaliumcarbonat og inndampes til tørrhet under nedsatt trykk. Residuet kromatograferes på aluminiumoxyd (aktivitet III). Der elueres med benzen, idet fraksjoner på IO ml oppsamles. Den ønskede apovincaminsyre-butylester fåes i fraksjon 1 som inndampes til tørrhet under nedsatt trykk. Utbytte: 0,049- Produktets egenskaper er de samme som angitt i eksempel 6. The progress of the reaction is followed by thin-layer chromatography. After completion of the reaction, 10 ml of water is added to the reaction mixture, and then extracted with 3 x 10 ml of dichloromethane. The dichloromethane extract is combined, dried with anhydrous potassium carbonate and evaporated to dryness under reduced pressure. The residue is chromatographed on aluminum oxide (activity III). Elute with benzene, with fractions of 10 ml being collected. The desired apovincamic acid butyl ester is obtained in fraction 1, which is evaporated to dryness under reduced pressure. Yield: 0.049- The properties of the product are the same as stated in example 6.
Den erholdte ester kan på den i eksempel 5 beskrevne måte overføres til tartratet som har smeltepunkt 175°C; The ester obtained can be transferred in the manner described in example 5 to the tartrate, which has a melting point of 175°C;
[a]^° = 62,1° (c = 1, i pyridin). [α]^° = 62.1° (c = 1, in pyridine).
Eksempel 11 Example 11
1 g (0,0029 mol) vincaminsyre og 0,11 g (0,0027 mol) natriumhydroxyd oppløses i 200 ml vannfri ethanol. Oppløsningen gjøres svakt sur med eddiksyre og kokes så under tilbakeløp. Dannelsen av vincaminsyre-ethylester følges kromatografisk. 1 g (0.0029 mol) of vincamic acid and 0.11 g (0.0027 mol) of sodium hydroxide are dissolved in 200 ml of anhydrous ethanol. The solution is made slightly acidic with acetic acid and then boiled under reflux. The formation of vincamic acid ethyl ester is monitored chromatographically.
Efter 10 timers kokning inndampes oppløsningen til ca. 20 ml, tilsettes 500 ml destillert vann og d.erpå innstilles pH-verdien av oppløsningen på 8 i en skilletrakt med 5%-ig natronlut. Blandingen med dét dannede bunnfall ekstraheres med 5 x 200 ml diklormethan, de organiske faser forenes, tørres med vannfritt kaliumcarbonat, filtreres, og filtratet inndampes til tørrhet under nedsatt trykk. Residuet oppløses i 20 ml ethanol og krystalliseres ved O - 2°C. Som produkt fåes kromatografisk enhetlig vincaminsyre-ethylester. Utbytte: 40%, smp.: 244° C (Boetius); After 10 hours of boiling, the solution is evaporated to approx. 20 ml, 500 ml of distilled water is added and then the pH value of the solution is adjusted to 8 in a separatory funnel with 5% caustic soda. The mixture with the formed precipitate is extracted with 5 x 200 ml of dichloromethane, the organic phases are combined, dried with anhydrous potassium carbonate, filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 20 ml of ethanol and crystallized at 0 - 2°C. Chromatographically uniform vincamic acid ethyl ester is obtained as a product. Yield: 40%, mp: 244° C (Boetius);
[a]D= +63,6° (c = 1; i pyridin). [α]D= +63.6° (c = 1; in pyridine).
Eksempel 12 Example 12
0>5g (0,0014 mol) vincaminsyre og 0,05 g natriumhydroxyd oppløses i 60 ml ethanol. Oppløsningen tilsettes 0,2 g (0,0015 mol) benzylklorid, og blandingen kokes under tilbakeløp i 8 timer. Forløpet av forestringsreaksjonen kan følges ved tynnskikts- 0>5g (0.0014 mol) of vincamic acid and 0.05 g of sodium hydroxide are dissolved in 60 ml of ethanol. 0.2 g (0.0015 mol) of benzyl chloride is added to the solution, and the mixture is refluxed for 8 hours. The course of the esterification reaction can be followed by thin-layer
kromatografi. Efter avsluttet reaksjon avkjøles oppløsningen, chromatography. After completion of the reaction, the solution is cooled,
og ethanolen avdestilleres under nedsatt trykk. Det erholdte oljeaktige residuum tilsettes 30 ml 2%-ig svovelsyre, og derpå innstilles pH-verdien av den erholdte oppløsning på 8 med vandig 10%-ig natronlut. Den alkaliske oppløsning ekstraheres med 3 x 30 ml diklormethan. Den forenede organiske oppløsning tørres med vannfritt natriumsulfat, filtreres og inndampes til tørrhet under nedsatt trykk. Det erholdte tørre residuum renses ved kolonnekroma-tografi på aluminiumoxyd (efter Breckmann, aktivitet III). Det med benzen erholdte eluat gir produktet i fraksjon 8 - l6. Disse fraksjoner forenes og inndampes til tørrhet. Man får på denne måte 0,1 g vincaminsyre-benzylester. Produktet kan på den i eksempel 1 beskrevne måte overføres til tartratet. Kvaliteten av produktet er identisk med den for produktet i eksempel 1. and the ethanol is distilled off under reduced pressure. The obtained oily residue is added to 30 ml of 2% sulfuric acid, and then the pH value of the obtained solution is adjusted to 8 with aqueous 10% caustic soda. The alkaline solution is extracted with 3 x 30 ml of dichloromethane. The combined organic solution is dried with anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The dry residue obtained is purified by column chromatography on aluminum oxide (according to Breckmann, activity III). The eluate obtained with benzene gives the product in fractions 8 - 16. These fractions are combined and evaporated to dryness. In this way, 0.1 g of vincamic acid benzyl ester is obtained. The product can be transferred to the tartrate in the manner described in example 1. The quality of the product is identical to that of the product in example 1.
Eksempel 13 Example 13
Apovincaminsyre- ethylest er- methojodid Apovincamic acid - ethyl ester - methoiodide
1 g (0,0028 mol) apovincaminsyre-ethylester oppløses i 25 ml vannfri aceton, og 0,449(0,003 mol) methyljodid tilsettes til oppløsningen. Blandingen hensettes ved værelsetemperatur i 24 timer. I løpet av denne tid følges reaksjonen ved skiktkromato-graf i. Nålformige krystaller begynner å utskilles fra reaksjonsblandingen endog ved henstand ved-værelsetemperatur. Blandingen inndampes under nedsatt trykk til et sluttvolum på ca. 10 ml, og konsentratet hensettes for krystallisasjon ved 0 - 2°C i ca. 8~10 timer. Krystallene frafiltreres og vaskes noen ganger med kold aceton. 1,299(92%) apovincaminsyre-ethylest er-methojodidfåes. Sm.p.: 204°C. 1 g (0.0028 mol) of apovincamic acid ethyl ester is dissolved in 25 ml of anhydrous acetone, and 0.449 (0.003 mol) of methyl iodide is added to the solution. The mixture is left at room temperature for 24 hours. During this time, the reaction is monitored by layer chromatograph i. Needle-shaped crystals begin to separate from the reaction mixture even when allowed to stand at room temperature. The mixture is evaporated under reduced pressure to a final volume of approx. 10 ml, and the concentrate is set aside for crystallization at 0 - 2°C for approx. 8~10 hours. The crystals are filtered off and washed several times with cold acetone. 1.299 (92%) of apovincamic acid ethyl ester methoiodide is obtained. Melting point: 204°C.
Elementæranalyse: Elemental analysis:
Beregnet: c = 56,12% H = 5,93% N = 5,69% I = 25,77% Calculated: c = 56.12% H = 5.93% N = 5.69% I = 25.77%
Funnet: C = 56,02% H = 5,88% N = 5,70% I=25,79% Found: C = 56.02% H = 5.88% N = 5.70% I=25.79%
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ZA (1) | ZA726619B (en) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2259612B1 (en) * | 1974-01-31 | 1977-09-09 | Synthelabo | |
HU171662B (en) * | 1975-07-18 | 1978-02-28 | Richter Gedeon Vegyeszet | Process for preparing new optically active derivatives of apovincaminol and acid addition salts thereof |
GB1549501A (en) * | 1976-06-03 | 1979-08-08 | Mora E | Adducts of vincamine and apovincamine |
HU177370B (en) * | 1977-07-27 | 1981-09-28 | Richter Gedeon Vegyeszet | Process for producing new bracket-cross-bracket-vincaminol-esters |
JPS55100383A (en) * | 1979-01-25 | 1980-07-31 | Sumitomo Chem Co Ltd | Preparation of novel nitrogen-containing polycyclic compound |
AU532001B2 (en) * | 1978-11-20 | 1983-09-15 | Sumitomo Chemical Company, Limited | Polycyclic indole derivatives |
CH645269A5 (en) * | 1979-08-16 | 1984-09-28 | Richter Gedeon Vegyeszet | Medicine for the skin, and process for its production |
JPS56161388A (en) * | 1980-05-16 | 1981-12-11 | Nippon Zoki Pharmaceut Co Ltd | Novel vincamine derivative |
IT1148733B (en) * | 1980-11-14 | 1986-12-03 | Medea Res Srl | VINCAMIN DERIVATIVES, METHOD FOR ITS PHARMACEUTICAL PREPARATION AND COMPOSITION THAT CONTAIN IT |
HU192013B (en) * | 1984-04-25 | 1987-04-28 | Richter Gedeon Vegyeszet | Process for production of new aporincavinol esther derivatives |
HU191938B (en) * | 1984-07-11 | 1987-04-28 | Andras Vedres | Process for production of new derivatives of 9 and 11 nitro-apovincamin acid |
ES8604956A1 (en) * | 1985-11-20 | 1986-03-16 | Covex Sa | Process for the obtention of the ethyl ester of the apovincaminic acid |
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0
- BE BE790837D patent/BE790837A/en not_active IP Right Cessation
-
1971
- 1971-11-03 HU HURI454A patent/HU163434B/hu unknown
-
1972
- 1972-09-25 AT AT821872A patent/AT322118B/en not_active IP Right Cessation
- 1972-09-27 ZA ZA726619A patent/ZA726619B/en unknown
- 1972-09-28 IL IL40457A patent/IL40457A/en unknown
- 1972-09-28 AU AU47179/72A patent/AU469544B2/en not_active Expired
- 1972-09-28 NO NO3470/72A patent/NO136714C/en unknown
- 1972-09-28 GB GB4489272A patent/GB1405127A/en not_active Expired
- 1972-10-02 DD DD165983A patent/DD101895A5/xx unknown
- 1972-10-17 FR FR7236735A patent/FR2158229B1/fr not_active Expired
- 1972-10-18 PL PL1972173980A patent/PL84613B1/en unknown
- 1972-10-18 PL PL1972158330A patent/PL83604B1/en unknown
- 1972-10-20 CH CH1537172A patent/CH580628A5/xx not_active IP Right Cessation
- 1972-10-20 RO RO7200080703A patent/RO63055A/en unknown
- 1972-10-20 RO RO7272589A patent/RO62453A/en unknown
- 1972-10-21 EG EG439/72A patent/EG10707A/en active
- 1972-10-23 FI FI2929/72A patent/FI56687C/en active
- 1972-10-27 IN IN1758/72A patent/IN138719B/en unknown
- 1972-10-27 SE SE7213934A patent/SE402460B/en unknown
- 1972-10-30 JP JP47108028A patent/JPS5132640B2/ja not_active Expired
- 1972-10-30 NL NLAANVRAGE7214672,A patent/NL171584C/en not_active IP Right Cessation
- 1972-11-01 BG BG023710A patent/BG22830A3/en unknown
- 1972-11-01 BG BG021764A patent/BG20602A3/en unknown
- 1972-11-01 DK DK540472AA patent/DK140552B/en not_active IP Right Cessation
- 1972-11-01 BG BG023711A patent/BG25515A3/en unknown
- 1972-11-02 DE DE2265169A patent/DE2265169C3/en not_active Expired
- 1972-11-02 SU SU7201845297A patent/SU578005A3/en active
- 1972-11-02 DE DE2253750A patent/DE2253750C3/en not_active Expired
- 1972-11-02 DE DE2265138A patent/DE2265138C3/en not_active Expired
- 1972-11-02 ES ES408180A patent/ES408180A1/en not_active Expired
- 1972-11-02 CA CA155,420A patent/CA991187A/en not_active Expired
- 1972-11-03 YU YU2735/72A patent/YU36738B/en unknown
- 1972-11-03 CS CS727419A patent/CS191208B2/en unknown
-
1979
- 1979-01-04 KE KE2912A patent/KE2912A/en unknown
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