DE1060401B - Process for the preparation of 1- (carboxyalkyl) -piperazines and their esters effective against schistosomiasis - Google Patents
Process for the preparation of 1- (carboxyalkyl) -piperazines and their esters effective against schistosomiasisInfo
- Publication number
- DE1060401B DE1060401B DEF21553A DEF0021553A DE1060401B DE 1060401 B DE1060401 B DE 1060401B DE F21553 A DEF21553 A DE F21553A DE F0021553 A DEF0021553 A DE F0021553A DE 1060401 B DE1060401 B DE 1060401B
- Authority
- DE
- Germany
- Prior art keywords
- methylphenyl
- esters
- acid
- chloro
- piperazino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000002148 esters Chemical class 0.000 title claims description 17
- 238000000034 method Methods 0.000 title claims description 15
- 201000004409 schistosomiasis Diseases 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 3
- 125000004181 carboxyalkyl group Chemical group 0.000 title description 2
- -1 aliphatic alcohols Chemical class 0.000 claims description 12
- 150000003977 halocarboxylic acids Chemical class 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 150000007934 α,β-unsaturated carboxylic acids Chemical class 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000000155 melt Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- HZENZTPJJXKSDT-UHFFFAOYSA-N 1-(3-chloro-4-methylphenyl)piperazine Chemical compound C1=C(Cl)C(C)=CC=C1N1CCNCC1 HZENZTPJJXKSDT-UHFFFAOYSA-N 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 150000004885 piperazines Chemical class 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- FFOPEPMHKILNIT-UHFFFAOYSA-N Isopropyl butyrate Chemical compound CCCC(=O)OC(C)C FFOPEPMHKILNIT-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 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 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 2
- SWYYWGQORQVRBD-UHFFFAOYSA-N 1-(3-bromo-4-methylphenyl)piperazine Chemical compound C1=C(Br)C(C)=CC=C1N1CCNCC1 SWYYWGQORQVRBD-UHFFFAOYSA-N 0.000 description 1
- WMFATTFQNRPXBQ-UHFFFAOYSA-N 2-bromopentanoic acid Chemical compound CCCC(Br)C(O)=O WMFATTFQNRPXBQ-UHFFFAOYSA-N 0.000 description 1
- ATACSYDDCNWCLV-UHFFFAOYSA-N 2-chloroacetic acid;sodium Chemical compound [Na].OC(=O)CCl ATACSYDDCNWCLV-UHFFFAOYSA-N 0.000 description 1
- QEYMMOKECZBKAC-UHFFFAOYSA-N 3-chloropropanoic acid Chemical compound OC(=O)CCCl QEYMMOKECZBKAC-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- SBCFISMFQZTKRA-UHFFFAOYSA-N CC(C=CC(N1CCN(CC(OC)=O)CC1)=C1)=C1Cl Chemical compound CC(C=CC(N1CCN(CC(OC)=O)CC1)=C1)=C1Cl SBCFISMFQZTKRA-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000242678 Schistosoma Species 0.000 description 1
- 241000242680 Schistosoma mansoni Species 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 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
- 238000004519 manufacturing process Methods 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical class C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000001843 schistosomicidal effect Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von gegen Schistosomiasis wirksamen 1- (Carb oxyalkyl) -pip erazinen und deren Estern Es ist bekannt, daß gewisse Piperazinderivate bei der Bekämpfung von Blutparasiten Bedeutung erlangt haben. So wurden bereits in der USA.-Patentschrift 2 656 357 gegen Schistosomen-Infektionen wirksame Piperazinderivate beschrieben, und auch das schwedische Patent 136 102 hat die Herstellung von gegen Schistosomiasis wirksamen Piperazinabkömmlingen zum Gegenstand. Ferner wurden bereits bestimmte Abkömmlinge des Piperazins, beispielsweise das 1-Diäthyl-carbamino-4-methylpiperazin, als Mittel zur Bekämpfung von Filarien-Infektionen vorgeschlagen.Process for the preparation of 1- (Carb oxyalkyl) -pip erazinen and their esters It is known that certain piperazine derivatives have become important in the fight against blood parasites. So were already in U.S. Patent 2,656,357, piperazine derivatives effective against schistosomal infections described, and also the Swedish patent 136 102 has the production of against Schistosomiasis effective piperazine derivatives the subject. Furthermore, have already been certain derivatives of piperazine, for example 1-diethyl-carbamino-4-methylpiperazine, Proposed as a means of combating filarian infections.
Es wurde nun gefunden, daß man zu gegen Schistosomiasis wirksamen 1-Carboxyalkylpiperazinen und deren Estern der allgemeinen Formel in der R einen bis 3 Kohlenstoffatome enthaltenden geraden oder verzweigten Alkylrest bedeutet, der durch eine oder zwei Carboxylgruppen substituiert ist, wobei letztere mit aliphatischen Alkoholen, die eine gerade oder verzweigte Kohlenstoffkette von 1 bis 5 Kohlenstoffatomen besitzen, verestert sein können, und Hal Chlor oder Brom bedeutet, gelangen kann, indem man 1-(3'-Halogen-4'-methylphenyl)-piperazine mit Halogencarbonsäuren bzw. deren Estern der allgemeinen Formel X - R, in der R die angegebene Bedeutung hat und X für ein Halogenatom, vorzugsweise Chlor oder Brom, steht, oder mit entsprechenden a,ß-ungesättigten Carbonsäuren bzw. deren Estern umsetzt und gegebenenfalls die erhaltenen Ester verseift.It has now been found that 1-carboxyalkylpiperazines and their esters of the general formula which are effective against schistosomiasis can be obtained in which R is a straight or branched alkyl radical containing up to 3 carbon atoms, which is substituted by one or two carboxyl groups, the latter being esterified with aliphatic alcohols having a straight or branched carbon chain of 1 to 5 carbon atoms, and Hal chlorine or Means bromine, can be achieved by 1- (3'-halo-4'-methylphenyl) -piperazines with halocarboxylic acids or their esters of the general formula X - R, in which R has the meaning given and X is a halogen atom, preferably Chlorine or bromine, or with corresponding α, β-unsaturated carboxylic acids or their esters and optionally saponified the esters obtained.
Die als Ausgangsmaterial verwendeten 1-(3'-Halogen-4'-methylphenyl)-piperazine können nach den in den Patenten 1019 309 und 1019 308 beschriebenen Verfahren hergestellt werden.The 1- (3'-halo-4'-methylphenyl) used as starting material piperazines can be prepared by the methods described in 1019 309 and 1 019 308 are prepared in the patents.
Als Halogencarbonsäuren bzw. deren Ester oder a,ß-ungesättigte Carbonsäuren bzw. deren Ester kommen beispielsweise Chloressigsäure, Bromessigsäure, a-Brompropionsäure, ß-Chlorpropionsäure, a-Brombuttersäure, a-Bromisobuttersäure, y-Chlorbuttersäure, a-Bromvaleriansäure, Acrylsäure, Crotonsäure, Maleinsäure, Fumarsäure sowie deren Ester mit aliphatischen Alkoholen in Betracht.As halocarboxylic acids or their esters or α, ß-unsaturated carboxylic acids or their esters come, for example, chloroacetic acid, bromoacetic acid, a-bromopropionic acid, ß-chloropropionic acid, a-bromobutyric acid, a-bromoisobutyric acid, y-chlorobutyric acid, α-bromovaleric acid, acrylic acid, crotonic acid, maleic acid, fumaric acid and their Esters with aliphatic alcohols are considered.
Das Verfahren gemäß der Erfindung läßt sich in an sich bekannter Weise so durchführen, daß man auf die 1- (3' -Halogen - 4' - methylphenyl) - piperazine Halogencarbonsäuren oder deren Alkylester einwirken läßt. Man arbeitet bei erhöhter Temperatur und kann die Umsetzung in Abwesenheit oder in Gegenwart von Lösungsmitteln vornehmen. Als solche kommen beispielsweise reine oder mit Wasser verdünnte Alkohole in Frage. Zur Bindung der abgespaltenen Halogenwasserstoffsäure kann man eine basische Verbindung, wie Alkalicarbonate, Alkalihydroxyde oder tertiäre Basen zusetzen, oder die Halogencarbonsäuren gleich in Form ihrer Alkalisalze zur Reaktion bringen.The method according to the invention can be carried out in a manner known per se perform so that one on the 1- (3 '-halogen - 4' - methylphenyl) - piperazine Allow halocarboxylic acids or their alkyl esters to act. One works at heightened Temperature and can carry out the reaction in the absence or in the presence of solvents make. Examples of such alcohols are pure alcohols or alcohols diluted with water in question. To bind the split off hydrohalic acid one can use a basic Add compounds such as alkali carbonates, alkali hydroxides or tertiary bases, or bring the halocarboxylic acids to reaction in the form of their alkali metal salts.
Eine weitere Ausführungsform des erfindungsgemäßen Verfahrens besteht darin, daß man die 1-(3'-Halogen-4'-methylphenyl)-piperazine mit a,ß-ungesättigten Carbonsäuren oder deren Alkylestern in an sich bekannter Weise zur Umsetzung bringt. Dabei arbeitet man bei erhöhten Temperaturen, vorzugsweise bei 80 bis 120°C. Die Reaktion kann in Abwesenheit oder in Gegenwart von Lösungsmitteln, wie niedrigen Alkoholen, vorgenommen werden.There is another embodiment of the method according to the invention in that the 1- (3'-halo-4'-methylphenyl) -piperazines with a, ß-unsaturated Brings carboxylic acids or their alkyl esters in a known manner to implement. The process is carried out at elevated temperatures, preferably from 80 to 120.degree. the Reaction can take place in the absence or in the presence of solvents such as low Alcohols.
Die Veresterung der erhaltenen Carbonsäuren erfolgt nach einem der üblichen Verfahren, z. B. durch Erhitzen mit dem entsprechenden Alkohol in Gegenwart wasserfreier Mineralsäuren, wie Chlorwasserstoff oder Schwefelsäure, oder durch Umsetzung mit Alkylierungsmitteln, wie Diazomethan oder Dialkylsulfat.The esterification of the carboxylic acids obtained takes place according to one of the usual procedures, e.g. B. by heating with the appropriate alcohol in the presence anhydrous mineral acids, such as hydrogen chloride or sulfuric acid, or by Reaction with alkylating agents such as diazomethane or dialkyl sulfate.
Werden nach einer der geschilderten Ausführungsformen des Verfahrens Carbonsäureester erhalten, so können diese wie üblich, z. B. durch Erhitzen mit wäßrigen oder alkoholischen Alkalien, verseift werden.Are according to one of the described embodiments of the method Carboxylic acid esters obtained, they can as usual, for. B. by heating with aqueous or alcoholic alkalis, are saponified.
Die nach dem Verfahren gemäß der Erfindung erhaltenen Carbonsäuren stellen meist farblose kristalline Produkte dar, die sich zum Teil in Wasser lösen. Mit Alkalien, wie Natriumhydroxyd, bilden sie leicht wasserlösliche Salze. Die Ester dieser Verbindungen mit aliphatischen Alkoholen sind farblose kristalline Körper oder farblose bis hellgelbe Öle. Sie lösen sich im allgemeinen gut in den gebräuchlichen organischen Lösungsmitteln, nicht jedoch in Wasser. Mit anorganischen oder organischen Säuren bilden sie meist gut kristallisierende, wasserlösliche Salze.The carboxylic acids obtained by the process according to the invention mostly represent colorless crystalline products, some of which dissolve in water. With alkalis such as sodium hydroxide, they form easily water-soluble salts. the Esters of these compounds with aliphatic alcohols are colorless crystalline Body or colorless to light yellow oils. They generally dissolve well in the common organic solvents, but not in water. With inorganic or organic acids, they usually form well-crystallizing, water-soluble salts.
Die Verfahrenserzeugnisse stellen wertvolle Heilmittel dar. Sie eignen sich insbesondere zur Bekämpfung von Schistosomen-Infektionen der VV armblüter und sind hinsichtlich dieser Eigenschaften der zu Beginn der Beschreibung erwähnten bekannten Verbindungen erheblich überlegen. Beispielsweise konnte an Hand von chemotherapeutischen Vergleichsversuchen gezeigt werden, daß dem aus USA.-Patent 2 656 357 bekannten 1-[1'-(4'-Methyl-piperazyl)]-4-methylthioxanthon nur eine sehr geringe Wirkung gegen Schistosoma mansoni zukommt, während das aus dem schwedischen Patent l36102 bekannte 1-Diäthyl-thiocarbamino-4-methylpiperazinhydrochlorid sowie das anfangs erwähnte, bereits bekannte 1-Diäthyl-carbamino-4-methylpiperazin unter den Versuchsbedingungen überhaupt keine schistosomicide Eigenschaften aufwiesen.The products of the process are valuable remedies. They are particularly suitable for combating schistosome infections of the VV poor blood and are considerably superior to the known compounds mentioned at the beginning of the description with regard to these properties. For example, it could be shown of chemotherapeutic comparative experiments on hand that the from USA. Patent 2,656,357 known 1- [1 '- (4'-methyl-piperazyl)] - 4-methylthioxanthone only a very low activity against Schistosoma mansoni belongs, while the 1-diethyl-thiocarbamino-4-methylpiperazine hydrochloride known from Swedish patent 136102 and the already known 1-diethyl-carbamino-4-methylpiperazine mentioned at the beginning did not show any schistosomicidal properties under the test conditions.
Gegenüber anderen bei Schistosomiasis wirksamen Stoffen zeichnen sich die Verfahrenserzeugnisse weiterhin durch eine sehr gute Verträglichkeit und durch die Möglichkeit einer parenteralen Applikation aus.Compared to other substances effective in schistosomiasis stand out the process products continue to be very well tolerated and by the possibility of a parenteral application.
Beispiel 1 180 g 1-(3'-Chlor-4'-methylphenyl)-piperazin werden in 300 ccm Äthylalkohol und 450 ccm Wasser gelöst. Man gibt hierzu 110 g Chloressigsäurenatrium, erhitzt 1 Stunde auf 60°C und 1 Stunde auf 100°C, wobei der Alkohol verdampft, fügt dann 150 ccm Eisessig zu und läßt auskristallisieren. Man kristallisiert das Rohprodukt zweimal aus einem Gemisch Eisessig-Wasser 1 : 1 um und erhält 181 g reine, mit 1 Mol Essigsäure kristallisierende 4-(3'-Chlor-4'-methylphenyl)-piperazino-essigsäure in farblosen Kristallen, die bei 200°C nicht sehr scharf schmelzen. Die Verbindung kann auch frei von Essigsäure durch Kristallisieren aus Wasser oder Methanol erhalten werden: Schmelzpunkt 200 bis 201°C nach geringer Zersetzung. Das Natriumsalz, aus Alkohol-Wasser 5:1 umkristallisiert, enthält 4 Mol Kristallwasser und zersetzt sich zwischen 310 und 315°C.Example 1 180 g of 1- (3'-chloro-4'-methylphenyl) piperazine are dissolved in 300 cc of ethyl alcohol and 450 cc of water. 110 g of sodium chloroacetic acid are added, the mixture is heated at 60 ° C. for 1 hour and at 100 ° C. for 1 hour, the alcohol evaporating, then 150 cc of glacial acetic acid is added and the mixture is allowed to crystallize. The crude product is recrystallized twice from a mixture of glacial acetic acid and water 1: 1 and 181 g of pure 4- (3'-chloro-4'-methylphenyl) -piperazino-acetic acid, crystallizing with 1 mol of acetic acid, are obtained in colorless crystals, which at 200 ° C does not melt very sharply. The compound can also be obtained free of acetic acid by crystallization from water or methanol: melting point 200 to 201 ° C. after slight decomposition. The sodium salt, recrystallized from alcohol-water 5: 1, contains 4 moles of water of crystallization and decomposes between 310 and 315 ° C.
Eine Lösung von 40 g 4-(3'-Chlor-4'-methylphenyl)-piperazineessigsäure - 1 Essigsäure in 160 ccm absolutem Methanol wird mit Salzsäuregas gesättigt und 4 Stunden unter Rückfluß gekocht. Man kühlt auf 0° C, saugt das Salz ab, zerlegt es mit 2 n-Ammoniaklösung und nimmt die Esterbase in Äther auf. Nach dem Trocknen und Abdampfen des Lösungsmittels erhält man 27 g reinen 4-(3'-Chlor-4'-methylphenyl)-piperazino-essigsäuremethylester vom Schmelzpunkt 78 bis 79°C in farblosen Kristallen. Man kann ihn zur Reinigung aus Methanol umkristallisieren.A solution of 40 g of 4- (3'-chloro-4'-methylphenyl) piperazine acetic acid - 1 acetic acid in 160 ccm of absolute methanol is saturated with hydrochloric acid gas and Boiled under reflux for 4 hours. It is cooled to 0 ° C., the salt is filtered off with suction and dismantled it with 2N ammonia solution and takes up the ester base in ether. After drying and evaporation of the solvent, 27 g of pure 4- (3'-chloro-4'-methylphenyl) -piperazino-acetic acid methyl ester are obtained from melting point 78 to 79 ° C in colorless crystals. You can use it for cleaning recrystallize from methanol.
Unter Verwendung des jeweils entsprechenden Alkohols werden nach dem gleichen Verfahren erhalten 4- (3'- Chlor -4'- methylphenyl) -piperazino - essigsäureäthylester, umkristallisierbar aus Äthanol, Schmelzpunkt 64 bis 65°C; 4- (3'- Chlor -4'- methylphenyl) -piperazino - essigsäurebutylester, umkristallisierbar aus Methanol, Schmelzpunkt 62 bis 63'C; 4- (3'- Chlor -4'- methylphenyl) -piperazino - essigsäureisoamylester, der nach der Reinigung durch Vakuumdestillation (Kp. o,s = 185°C) bei 49 bis 50°C schmilzt. Er kann aus einem Gemisch von Äthanol-Wasser 5 : 1 umkristallisiert werden. Beispiel 2 104g 1-(3'-Chlor-4'-methylphenyl)-piperazin und 76g einer 50 °/oigen wäßrigen Acrylsäurelösung werden vermischt, wobei starke Erwärmung eintritt, und 3 Stunden auf dem Dampfbad erhitzt. Nach kurzer Zeit beginnt die Kristallisati-on, und schließlich ist das ganze Gemisch zu einem harten Kristallkuchen erstarrt. Nach dem Umkristallisieren aus Äthanol erhält man 112 g ß-[4-(3'-Chlor-4'-methylphenyl)-piperazino]-propionsäure in Form farbloser Kristalle vom Schmelzpunkt 170 bis 173°C.Using the corresponding alcohol in each case, 4- (3'-chloro -4'-methylphenyl) -piperazino - ethyl acetate, recrystallizable from ethanol, melting point 64 to 65 ° C; are obtained by the same process; 4- (3'-chloro -4'-methylphenyl) -piperazino-acetic acid butyl ester, recrystallizable from methanol, melting point 62 to 63'C; 4- (3'-chloro -4'-methylphenyl) -piperazino-acetic acid isoamyl ester, which melts at 49 to 50 ° C. after purification by vacuum distillation (boiling point o, s = 185 ° C.). It can be recrystallized from a mixture of ethanol-water 5: 1. Example 2 104 g of 1- (3'-chloro-4'-methylphenyl) piperazine and 76 g of a 50% strength aqueous acrylic acid solution are mixed, with intense heating occurring, and heated on the steam bath for 3 hours. After a short time, the crystallization begins, and finally the whole mixture has solidified into a hard crystal cake. After recrystallization from ethanol, 112 g of β- [4- (3'-chloro-4'-methylphenyl) piperazino] propionic acid are obtained in the form of colorless crystals with a melting point of 170 to 173 ° C.
Durch Veresterung der ß-[4-(3'-Chlor-4'-methylphenyl)-piperazino]-propionsäure analog der im Beispiel 1 angegebenen Vorschrift werden erhalten ß- [4- (3'-Chlor-4'-methylphenyl) -piperazino] -propionsäurepropylester: Farbloses Öl vom Kp. s = 190°C. Neutralisiert man die Lösung der Esterbase in Aceton mit alkoholischer Salzsäure, so erhält man das Hydrochlorid als farblose glänzende Plättchen, die, aus Methanol umkristallisiert, bei 205 bis 207°C unter Zersetzung schmelzen; ß- [4- (3'-Chlor-4'-methylphenyl) -piperazino] -propionsäurebutylester: Farbloses Öl vom Kp. ., = 254 bis 256°C, dessen Hydrochlorid bei 199 bis 203°C unter Zersetzung schmilzt; ß-[4- (3' -Chlor-4' -methylphenyl) -piperazino] -propionsäureamylester: Gelbliches Öl vom Kp. 7,5 = 257 bis 261°C, dessen Hydrochlorid unter bereits vorher beginnender Zersetzung bei 199 bis 202°C schmilzt.By esterification of ß- [4- (3'-chloro-4'-methylphenyl) -piperazino] -propionic acid analogously to the procedure given in Example 1 are obtained ß- [4- (3'-chloro-4'-methylphenyl) -piperazino] -propionic acid propyl ester: Colorless oil, b.p. s = 190 ° C. Neutralized the solution of the ester base in acetone with alcoholic hydrochloric acid is obtained the hydrochloride as colorless, shiny platelets which, recrystallized from methanol, melt at 205 to 207 ° C with decomposition; ß- [4- (3'-chloro-4'-methylphenyl) -piperazino] -propionic acid butyl ester: Colorless oil of bp., = 254 to 256 ° C, its Hydrochloride melts at 199 to 203 ° C with decomposition; ß- [4- (3 '-chloro-4' -methylphenyl) -piperazino] -propionic acid amyl ester: yellowish oil with a b.p. 7.5 = 257 to 261 ° C, its hydrochloride with already beginning decomposition at 199 to 202 ° C melts.
Beispiel 3 Man erhitzt 42 g 1-(3'-Chlor-4'-methylphenyl)-piperazin mit 17 g Acrylsäuremethylester 3 Stunden auf dem Dampfbad und kristallisiert die erhaltene Schmelze nach dem Erkalten aus Petroläther um. Man erhält so den ß-[4-(3'-Chlor-4'-methylphenyl)-piperazino]-propionsäuremethylester in Form farbloser Kristalle, die bei 50 bis 52°C schmelzen.Example 3 42 g of 1- (3'-chloro-4'-methylphenyl) piperazine are heated with 17 g of methyl acrylate for 3 hours on the steam bath and the crystallized obtained melt after cooling from petroleum ether. The methyl β- [4- (3'-chloro-4'-methylphenyl) piperazino] propionate is obtained in this way in the form of colorless crystals that melt at 50 to 52 ° C.
Beispiel 4 Man mischt 45 g 1-(3'-Brom-4'-methylphenyl)-piperazin mit 27 g einer 50°/jgen wäßrigen Acrylsäurelösung und erhitzt 3 Stunden auf dem Dampfbad. Dabei erstarrt das Gemisch kristallin. Nach dem Umkristallisieren aus Äthanol erhält man 37 g ß-[4-(3'-Brom-4'-methylphenyl)-piperazino]-propionsäure als farblose Kristalle vom Schmelzpunkt 167 bis 169°C.Example 4 45 g of 1- (3'-bromo-4'-methylphenyl) piperazine are mixed in 27 g of a 50% aqueous acrylic acid solution and heated for 3 hours on the steam bath. The mixture solidifies in crystalline form. Obtained after recrystallization from ethanol 37 g of β- [4- (3'-bromo-4'-methylphenyl) piperazino] propionic acid are obtained as colorless crystals from melting point 167 to 169 ° C.
Bei der Veresterung mit Isoamylalkohol nach der im Beispiel l angegebenen Vorschrift entsteht der ß-[4-(3'-Brom-4'-methylphenyl)-piperazino]-propionsäureisoamylester als hellgelbes Öl vom Kp. s = 255 bis 256°C. Das Hydrochlorid bildet farblose Kristalle und schmilzt bei 208 bis 212°C unter Dunkelfärbung.In the case of the esterification with isoamyl alcohol according to the one specified in Example l The isoamyl ß- [4- (3'-Bromo-4'-methylphenyl) piperazino] propionate is produced as a light yellow oil with a b.p. s = 255 to 256 ° C. The hydrochloride forms colorless crystals and melts at 208 to 212 ° C with a dark color.
Beispiel 5 165g 1-(3'-Chlor-4'-methylphenyl)-piperazinund 119,6 g Fumarsäuredimethylester werden in 600 ccm Methanol 8 Stunden unter Rückfluß gekocht. Man saugt heiß ab, läßt auskristallisieren und erhält 237g 4-(3'-Chlor-4'-methylphenyl)-piperazino-bernsteinsäuredimethylester vom Schmelzpunkt 114 bis 115,5°C. Aus Methanol umkristallisiert, schmilzt der gereinigte Ester bei 115 bis 116° C.Example 5 165g of 1- (3'-chloro-4'-methylphenyl) -piperazine and 119.6g Fumaric acid dimethyl ester is refluxed for 8 hours in 600 cc of methanol. It is filtered off with suction while hot, allowed to crystallize and 237 g of dimethyl 4- (3'-chloro-4'-methylphenyl) piperazino succinate are obtained from melting point 114 to 115.5 ° C. Recrystallized from methanol, the purified one melts Ester at 115 to 116 ° C.
71 g dieses Dimethylesters werden zur Verseifung 45 Minuten in einer Lösung von 28 g Ätzkali in 40 ccm Wasser und 200 ccm Methanol zum Sieden erhitzt, wobei das verdampfende Methanol durch insgesamt 160 ccm Wasser ersetzt wird. Die heiße Lösung wird mit Tierkohle geklärt, mit 70 ccm Eisessig schwach angesäuert und geimpft. Nach 15 Stunden wird abgesaugt und der ausgefallene Niederschlag aus Eisessig-Wasser 1 : 1 umkristallisiert. Man erhält 44,5 g 4-(3'-Chlor-4'-methylphenyl)-piperazino-bernsteinsäure, die bei 187 bis 188'C nicht sehr scharf unter Zersetzung schmilzt. Das Dinatriumsalz kann aus der wäßrigen Lösung durch Ausfällen mit Äthanol gewonnen werden.71 g of this dimethyl ester for saponification 45 minutes in a Solution of 28 g caustic potash in 40 ccm water and 200 ccm methanol heated to the boil, the evaporating methanol is replaced by a total of 160 ccm of water. the The hot solution is clarified with animal charcoal and weakly acidified with 70 cc of glacial acetic acid and vaccinated. After 15 hours, the product is filtered off with suction and the precipitate formed Recrystallized glacial acetic acid-water 1: 1. 44.5 g of 4- (3'-chloro-4'-methylphenyl) piperazino succinic acid are obtained, which does not melt very sharply with decomposition at 187 to 188 ° C. The disodium salt can be obtained from the aqueous solution by precipitation with ethanol.
Beispiel 6 84g 1-(3'-Chlor-4'-methylphenyl)-piperazin und 40g Crotonsäure werden miteinander 8 Stunden auf dem Dampfbad erhitzt, wobei man öfter mit dem Glasstab umrührt. Es bildet sich schließlich eine zähe Schmelze, die man noch warm in 400 ccm Äthylacetat löst. Nach kurzer Zeit setzt Kristallisation ein. Zu ihrer Vervollständigung läßt man einige Stunden stehen und saugt dann ab. Man erhält 105 g rohe ß-[3-(3'-Chlor-4'-methylphenyl)-piperazino]-buttersäure, die durch Umkristallisieren aus Aceton gereinigt werden kann. Die farblosen Kristalle schmelzen dann bei 135 bis 137°C.Example 6 84g of 1- (3'-chloro-4'-methylphenyl) -piperazine and 40 g of crotonic acid are heated together eight hours on the steam bath to give stirs frequently with a glass rod. Finally a viscous melt is formed, which is dissolved in 400 cc of ethyl acetate while it is still warm. After a short time, crystallization sets in. To complete it, leave it to stand for a few hours and then vacuum. 105 g of crude β- [3- (3'-chloro-4'-methylphenyl) piperazino] butyric acid are obtained, which can be purified by recrystallization from acetone. The colorless crystals then melt at 135 to 137 ° C.
Durch Veresterung der ß-[4-(3'-Chlor-4'-methylphenyl)-piperazino]-buttersäure analog der im Beispiel 1 angegebenen Vorschrift werden erhalten: ß- [4- (3'-Chlor-4' -methylphenyl) -piperazino] -buttersäure-isopropylester: Hellgelbes Öl vom Kp.l = 205 bis 207°C. Das Hydrochlorid, aus Aceton umkristallisiert, schmilzt bei 181 bis 183'C-ß- [4- (3'- Chlor-4'- methylphenyl) -piperazino] -buttersäure-isoamylester: Hellgelbes Öl vom Kp.3 = 248 bis 250°C. Das Hydrochlorid schmilzt bei 190 bis 191°C; ß - [4 - (3'- Chlor -4'- methylphenyl) -piperazino] -buttersäure-2"-äthyl-butylester: Gelbes Öl vom Kp.l,s = 240 bis 242°C. Das Hydrochlorid schmilzt nach dem Umkristallisieren aus einem Gemisch aus Aceton und Äther bei 175 bis 177°C.By esterification of ß- [4- (3'-chloro-4'-methylphenyl) -piperazino] -butyric acid analogously to the procedure given in Example 1, the following are obtained: ß- [4- (3'-chloro-4 ' methylphenyl) piperazino] butyric acid isopropyl ester: light yellow oil from Kp.l = 205 to 207 ° C. The hydrochloride, recrystallized from acetone, melts at 181 to 183'C-ß- [4- (3'-chloro-4'-methylphenyl) -piperazino] -butyric acid isoamyl ester: Light yellow oil with a boiling point of 3 = 248 to 250 ° C. The hydrochloride melts at 190 to 191 ° C; ß - [4 - (3'-chloro -4'-methylphenyl) -piperazino] -butyric acid-2 "-ethyl-butyl ester: Yellow oil of bp 1, s = 240 to 242 ° C. The hydrochloride melts after recrystallization from a mixture of acetone and ether at 175 to 177 ° C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF21553A DE1060401B (en) | 1956-11-02 | 1956-11-02 | Process for the preparation of 1- (carboxyalkyl) -piperazines and their esters effective against schistosomiasis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF21553A DE1060401B (en) | 1956-11-02 | 1956-11-02 | Process for the preparation of 1- (carboxyalkyl) -piperazines and their esters effective against schistosomiasis |
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| Publication Number | Publication Date |
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| DE1060401B true DE1060401B (en) | 1959-07-02 |
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| DEF21553A Pending DE1060401B (en) | 1956-11-02 | 1956-11-02 | Process for the preparation of 1- (carboxyalkyl) -piperazines and their esters effective against schistosomiasis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1197461B (en) * | 1962-02-23 | 1965-07-29 | Abbott Lab | Process for the preparation of 1,4-diazine derivatives |
| DE1285476B (en) * | 1964-07-21 | 1968-12-19 | Lilly Co Eli | Process for the preparation of bis-ª ‰ - (4-arylpiperazino) -aethylsulfonen |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2656357A (en) * | 1952-08-08 | 1953-10-20 | American Cyanamid Co | 1-piperazyl-4-methylthioxanthones and method of preparing same |
-
1956
- 1956-11-02 DE DEF21553A patent/DE1060401B/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2656357A (en) * | 1952-08-08 | 1953-10-20 | American Cyanamid Co | 1-piperazyl-4-methylthioxanthones and method of preparing same |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1197461B (en) * | 1962-02-23 | 1965-07-29 | Abbott Lab | Process for the preparation of 1,4-diazine derivatives |
| DE1285476B (en) * | 1964-07-21 | 1968-12-19 | Lilly Co Eli | Process for the preparation of bis-ª ‰ - (4-arylpiperazino) -aethylsulfonen |
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