US2877225A - Preparation of normal-alkyl reserpates and alkyl deserpidates - Google Patents
Preparation of normal-alkyl reserpates and alkyl deserpidates Download PDFInfo
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- US2877225A US2877225A US576834A US57683456A US2877225A US 2877225 A US2877225 A US 2877225A US 576834 A US576834 A US 576834A US 57683456 A US57683456 A US 57683456A US 2877225 A US2877225 A US 2877225A
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- 125000000217 alkyl group Chemical group 0.000 title description 4
- 238000002360 preparation method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 4
- -1 acyl radical Chemical class 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000001624 sedative effect Effects 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 2
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- 206010029216 Nervousness Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 208000013200 Stress disease Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- VDVJGIYXDVPQLP-UHFFFAOYSA-N piperonylic acid Chemical compound OC(=O)C1=CC=C2OCOC2=C1 VDVJGIYXDVPQLP-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 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
- IKAACYWAXDLDPM-UHFFFAOYSA-N 1,2,3,4,4a,5-hexahydronaphthalene Chemical compound C1=CCC2CCCCC2=C1 IKAACYWAXDLDPM-UHFFFAOYSA-N 0.000 description 1
- CNXZMGRWEYQCOQ-UHFFFAOYSA-N 2-methoxy-3-phenylprop-2-enoic acid Chemical compound COC(C(O)=O)=CC1=CC=CC=C1 CNXZMGRWEYQCOQ-UHFFFAOYSA-N 0.000 description 1
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Natural products COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 description 1
- YTFVRYKNXDADBI-SNAWJCMRSA-N 3,4,5-trimethoxycinnamic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC(OC)=C1OC YTFVRYKNXDADBI-SNAWJCMRSA-N 0.000 description 1
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- CVBMAZKKCSYWQR-BPJCFPRXSA-N Deserpidine 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)cccc3 CVBMAZKKCSYWQR-BPJCFPRXSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- DEUFHLFQPMURDV-UHFFFAOYSA-N Dimethoxycinnamic acid Chemical compound COC(C(O)=O)=C(OC)C1=CC=CC=C1 DEUFHLFQPMURDV-UHFFFAOYSA-N 0.000 description 1
- MDJQWFFIUHUJSB-MIESRMKVSA-N Methyl reserpate Natural products O=C(OC)[C@@H]1[C@@H](OC)[C@H](O)C[C@H]2[C@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 MDJQWFFIUHUJSB-MIESRMKVSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- YTFVRYKNXDADBI-UHFFFAOYSA-N O-Methylsinapic acid Natural products COC1=CC(C=CC(O)=O)=CC(OC)=C1OC YTFVRYKNXDADBI-UHFFFAOYSA-N 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 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
- MDJQWFFIUHUJSB-UHFFFAOYSA-N Reserpinsaeure-methylester Natural products COC1=CC=C2C(CCN3CC4CC(O)C(C(C4CC33)C(=O)OC)OC)=C3NC2=C1 MDJQWFFIUHUJSB-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
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid group Chemical class C(C=CC1=CC=CC=C1)(=O)O WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- ISMCNVNDWFIXLM-WCGOZPBSSA-N deserpidine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 ISMCNVNDWFIXLM-WCGOZPBSSA-N 0.000 description 1
- 229960001993 deserpidine Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical class OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 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
- 238000006798 ring closing metathesis reaction Methods 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
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D459/00—Heterocyclic compounds containing benz [g] indolo [2, 3-a] quinolizine ring systems, e.g. yohimbine; 16, 18-lactones thereof, e.g. reserpic acid lactone
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
United States PREPARATION OF NORMAL-ALKYL RESERPATES AND ALKYL DESERPIDATES William Irving Taylor, Summit, N. J., assignor to Ciba Pharmaceutical Products, Inc., Summit, N. 1., a corporafion of New Jersey No Drawing. Application April 9, 1956 Serial No. 576,834
6 Claims. (Cl. 260-287) This invention relates to a process for the production of organic compounds and the salts thereof. More particularly the invention concerns a process for the pro- :duction of compounds of the formula:
wherein R represents hydrogen or lower alkyl, R' stands for lower alkyl and R" for hydrogen or an acyl radical, and X represents the unsubstituted or substituted remainder of a benzene nucleus, and their salts. I
Lower alkyl radicals are for example methyl or ethyl, an acyl'radical is preferably that of an aliphatic, araliphatic, aromatic or heterocyclic acid, such as lower fatty acids, e. g. acetic or propionic acid, phenyl carboxylic acids, e. g. benzoi'c'* acid or preferably lower alkoxybenzoic acids such as 4-methoxy-benzoic acid, 3,4-dimethoxy-benzoic acid, 3,4,5-trimethoxy-benzoic acid, 3,4- methylenedioxy-benzoic acid, cinnamic acids, e. g. methoxy-cinnamic acid, dimethoxy-cinnamic acid or 3,4,5- trimethoxy-cinnamic acid, monocyclic heterocyclic carboxylic acids, e. g. furane-Z-carboxylic acid, thiophene- 2-car boxylic acid or nicotinic acid, or aryl sulfonic acids,
. e. g. toluene sulfonic acids.
It is known that the reduction of synthetically obtainable compounds of the formula:
'' wherein R, R and R have the above-mentioned meaning and A stands for an anion such as halogen ion, e. g. E} the chloride ion or a nitrate ion, with sodium bo1ohyatent'O L 2,877,225 Patented Mar. 10, 1959 Ice dride does not lead to the desired compounds having the 3-epi-alloyohimbane configuration like reser'pine, i. e.
v I I have now found that the B-unsaturated compounds of the formula:
wherein X, R,.l{, R" and A have the aforesaid meanings can be reduced to yield the desired compounds hav- 0 ing the 3-epi-alloyohimbane configuration, e. g.
This end can be achieved by liberating the free base of the quaternary starting material and reducing it with catalytically activated hydrogen under conditions which do not affect the double bonds in rings A and B.
' Agent's capable of liberating a base from a quaternary salt are alkaline agents, e. g. alkali or earth alkali metal hydroxides such as potassium or sodium hydroxide or ammonia suchas aqueous ammonia. The hydrogen used in the reduction step is activated by catalysts containing at least one element selected from the eighth group of the periodic system, e. g. platinum or palladium such as 10 percent palladium on charcoal. The reduction is carried out at room temperature or raised temperature, under normal or elevated pressure, preferably it is performed at an elevated temperature and under pressure.
The starting materials for the process of the invention are compounds of the formula:
- t H wherein A, X, R, R, and R" having the aforesaid meaning, preferably compounds of the formula:
OR ll wherein R," R and R" have the aforesaid meaning, R' stands for hydrogen or methoxy and A represents an anion such as a halogen ion, e. g. a chloride ion, or a nitrate ion. Thus, it is, for example, possible to liberate the free. base of a compound of the formula:.
by treatment with potassium hydroxide and reduce the compound thus obtained with hydrogen in the presence of percent palladium on charcoal so 'as to form the compound of the formula:
tic-a The. starting materials can be. used in the form of their optically active antipodes or in the form of the racemates. Depending on the choice. of the. starting material, the saturated final compound is .la'evo or dextro-rotary or 'racemic. Racemi'c mixtures can be resolved into t e optically active antipodes, such as reserpine or deserpidine which are laevo-rotary. The final products have valuable sedative activity and can be used as medicaments for the treatment of states of nervousness, anxiety, stress or mental disorders or can be used as intermediates in the production of such pharmacologically active compounds. The conversion of such intermediates into compounds having a sedative activity can be achieved according to known methods which are exemplified on the laevo-rotary compounds in copending application Serial No. 526,780, filed August 5, 1955, now Patent No. 2,824,874, by E. Schlittler et al. Thus in the final products being used as intermediates free carboxylic acids can be esterified by treatment with lower diazoalkancs and free hydroxy groups can be esterified, for example by treatment with acid halides, e. g. chlorides, or anhydrides, esterifiedhydroxyl. groups. can. be hydrolyzed, e. g. by treatment with alkali or alkaline earth hydroxides in lower alkanols, esterified hydroxyl groups may be alcoholized, e. g. by treatment with. alkali metal lower alcoholates, whereby lower carbalkoxy groups are transesterified. Thus, any of the compounds obtained can be converted into a compound having in 16-position a carbomethoxy group and in 18-position a trimethoxy hen zoyloxy group, which compounds show sedative activity and can be used as medicaments' for the treatment of states of nervousness, anxiety, stress or mental disorders.
The starting materials used in the process of' the invention are known and can for example be obtained in the following manner: quinone is reacted with 1,4butadiene-l-carboxylic acid in a Diels-Alder addition. The 6,9-dioxo-1,4,5a,6,9,10a-hexahydronaphthalene 1B carboxylic acid of the formula:
is then reduced with sodium. borohydride. to 6/8-hydroxy- 9-oxo 1,4,5a,6,9,10a hexahydronaphthalene 1/3 carboxylic acid, yielding by oxidation with perbenzoic acid 2,3a-oxido-6 8-hydroxy-9 oxo 1,2,3,4,5a,6,9,l0a octahydronaphthalene-lfi-carboxylic acid of the formula:
This compound, after esterification with diazomethane'is subjected to a Meerwein-Ponndorf reduction with aluminum isopropoxide to yield the (l13 9fx)-lactone of-3,6floxido-9p-hydroxy-3,4,5,6,9,10a hexahydronaphthalenelp-carboxylic acid of theformula:
hydronaphthalene-lfi-carboxylic acid. Oxidation with chromic' acidto' the corresponding 8-oXo-compou'nd, followed by reduction with zinc and acetic acid yields 2alower alkoxy-3p hydroxy-8-oxo-1,2,3,4,5a,8,9,-10a octahydronaphthalene-lfi-carboxylic acid of the formula:
0R Esterification with diazomethane, acetylation with acetic acid anhydride in pyridine, oxidation with osmium tetroxide and oxidative degradation with periodic acid gives 20:- lower alkoxy-35-acetoxy-Sfi-aldehydo-fl-carboxy methylcyclohexane-lfl-carboxylic acid methyl ester. This after esterification with diazomethane is condensed with a tryptamine of the formula:
wherein X has the aforesaid meaning to yield a compound of the formula:
Reduction with sodium borohydride and ring closure with heating results in a compound of the formula:
The conversion of an amide thus-obtained into a compound of the formula:
can be achieved by treatment with a ring-closing agent vsuch as phosphorous chloride.
' Salts ofthe products Obtained by the new. process can be made by methods known per se and are especially acid addition salts, e. g. those of the hydrohalic acids, e. g. hydrochloric acid, nitric acid, sulfuric acid, phosphoric acids, perchloric acid, acetic, citric, oxalic, tartaric, ascorbic, methane sulfonic, hydroxyethane sulfonic, p-toluene sulf onic acid or salicylic, p-amino-salicylic acidoracetylsalicylic acid. I
The invention comprises also any process, wherein an intermediate obtainable at any stage ofthe process is used as starting material and the remaining steps are carried out.
The example which follows is given in the way of illustration and shall not be construed as a limitation. Many modifications will appear obvious to the man skilled in the art and it is intended that such obvious modifications are also comprised by my invention. Temperatures are given in degrees centigrade.
Example 250 mg. of O-acetyl methyl didehydro-reserpate chloride is dissolved in 20 ml. of 50 percent aqueous ethanol and made alkaline by the addition of 5 ml. of 0.5 N potassium hydroxide. The solution is shaken for two and one-half hours in an atmosphere of hydrogen at 20 pounds pressure in the presence of mg. of 10 percent palladium on charcoal. After removal of the cat alyst the solution is diluted with 100 ml. of methylene chloride and washed twice with 50 ml. of water. The methylene chloride solution is dried over sodium sulfate and the solvent evaporated under reduced pressure. Chromatography over activated alumina yields the pure dl-O-acetyl methyl reserpate.
What is claimed is:
1. Process for the manufacture of a member of the group consisting of compounds of the formula in which R represents a member of the group consisting of hydrogen and methyl, R represents lower alkyl, and R' stands for a member of the group consisting of hydrogen and methoxy, and salts thereof, which comprises treating a member of the group consisting of compounds of the formula in which R, R and R' have the above-given meaning, R" stands for a member of the group consisting of hydrogen, the acyl radical of lower fatty acids, monocyclic aromatic carboxylic acids, monocyclic aryl-lower alkanoic acids, monocyclic heterocyclic carboxylic acids and monocyclic aryl sulfonic acids, and A represents an anion, and salts thereof, with hydrogen in the presence of a catalyst containing at least one element selected from the eighth. groupof the periodic system and in the presence .of an alkaline reagent.
2. Process according to claim 1, wherein A stands for a halogen anion.
with: hydrogen is carried,v out. in the pl' fimaqft' 'kl s siumhyd xid 6.- Pr cess according; to c m. 1,, whe e n re tment withhydrogen. is carried out; in the presence rota, catalyst 3. Process according to claim 2, wherein A stands for 5 containing palladium a chlorine anion.
4. Process according to claim 1, wherein treatme References Cited in the file of this patent with hydrogen is carried out in the presence of analkali metal hydroxide.
5; Process. according to claim 4, wherein treatme MacPhillamy: Journal of The American Chemical Som m ciety, vol. 77, pages 4335-4343 (August 1955).
Claims (1)
1. PROCESS FOR THE MANUFACTURE OF A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US576834A US2877225A (en) | 1956-04-09 | 1956-04-09 | Preparation of normal-alkyl reserpates and alkyl deserpidates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US576834A US2877225A (en) | 1956-04-09 | 1956-04-09 | Preparation of normal-alkyl reserpates and alkyl deserpidates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2877225A true US2877225A (en) | 1959-03-10 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US576834A Expired - Lifetime US2877225A (en) | 1956-04-09 | 1956-04-09 | Preparation of normal-alkyl reserpates and alkyl deserpidates |
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| Country | Link |
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| US (1) | US2877225A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2977365A (en) * | 1956-04-16 | 1961-03-28 | Olin Mathieson | 3-dehydroyohimbanes and their preparation |
| US2996508A (en) * | 1961-08-15 | Process of producing salts of a | ||
| US3031453A (en) * | 1962-04-24 | Benzyl keserpates and deserpidates | ||
| US3118893A (en) * | 1961-10-24 | 1964-01-21 | Ciba Geigy Corp | Isomerization of 3-epi-yohimbanes |
| US3126389A (en) * | 1964-03-24 | Related compounds | ||
| US3126391A (en) * | 1964-03-24 | Alkoxyalkyl ib-o-alkoxyalkyl - | ||
| US3126390A (en) * | 1964-03-24 | Ib-epi-deserpidates and derivatives | ||
| US3320260A (en) * | 1959-08-10 | 1967-05-16 | Warner Lambert Pharmaceutical | Benzocyclopentaindolizines and dibenzindolizines |
| US3341543A (en) * | 1963-01-02 | 1967-09-12 | Warner Lambert Pharmaceutical | Substituted quinolizines |
-
1956
- 1956-04-09 US US576834A patent/US2877225A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2996508A (en) * | 1961-08-15 | Process of producing salts of a | ||
| US3031453A (en) * | 1962-04-24 | Benzyl keserpates and deserpidates | ||
| US3126389A (en) * | 1964-03-24 | Related compounds | ||
| US3126391A (en) * | 1964-03-24 | Alkoxyalkyl ib-o-alkoxyalkyl - | ||
| US3126390A (en) * | 1964-03-24 | Ib-epi-deserpidates and derivatives | ||
| US2977365A (en) * | 1956-04-16 | 1961-03-28 | Olin Mathieson | 3-dehydroyohimbanes and their preparation |
| US3320260A (en) * | 1959-08-10 | 1967-05-16 | Warner Lambert Pharmaceutical | Benzocyclopentaindolizines and dibenzindolizines |
| US3118893A (en) * | 1961-10-24 | 1964-01-21 | Ciba Geigy Corp | Isomerization of 3-epi-yohimbanes |
| US3341543A (en) * | 1963-01-02 | 1967-09-12 | Warner Lambert Pharmaceutical | Substituted quinolizines |
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