NO129349B - - Google Patents
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- NO129349B NO129349B NO389070A NO389070A NO129349B NO 129349 B NO129349 B NO 129349B NO 389070 A NO389070 A NO 389070A NO 389070 A NO389070 A NO 389070A NO 129349 B NO129349 B NO 129349B
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- Norway
- Prior art keywords
- alkyl
- carbon atoms
- general formula
- piperazino
- dihydrodibenzo
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- 235000005985 organic acids Nutrition 0.000 claims description 3
- LWBLYEUAPNUGIP-UHFFFAOYSA-N 1-(5,6-dihydrobenzo[b][1]benzothiepin-5-yl)piperazine Chemical class C1CNCCN1C1C2=CC=CC=C2SC2=CC=CC=C2C1 LWBLYEUAPNUGIP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 18
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 11
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000008018 melting Effects 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 238000006386 neutralization reaction Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000011976 maleic acid Substances 0.000 description 6
- YITAORWEHMMACD-UHFFFAOYSA-N 1-(3-chloro-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)piperazine Chemical compound C12=CC(Cl)=CC=C2SC2=CC=CC=C2CC1N1CCNCC1 YITAORWEHMMACD-UHFFFAOYSA-N 0.000 description 4
- FKPSBYZGRQJIMO-UHFFFAOYSA-M benzyl(triethyl)azanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC1=CC=CC=C1 FKPSBYZGRQJIMO-UHFFFAOYSA-M 0.000 description 4
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 4
- 229960001076 chlorpromazine Drugs 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- KUIZKZHDMPERHR-UHFFFAOYSA-N 1-phenylprop-2-en-1-one Chemical compound C=CC(=O)C1=CC=CC=C1 KUIZKZHDMPERHR-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 208000009132 Catalepsy Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 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
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- -1 alkyl vinyl ketones Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000002903 catalepsic effect Effects 0.000 description 1
- 239000003874 central nervous system depressant Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/14—[b,f]-condensed
Description
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av nye 10-piperazino-10,ll-dihydrodibenzo-[b,f]-thiepiner av den generelle formel: The present invention relates to a process for the production of new 10-piperazino-10,11-dihydrodibenzo-[b,f]-thiepines of the general formula:
hvor where
: R"*" er halogen, ;R er -cyano, -C00H eller -COOR^, hvor er alkyl me'd 1 - h carbonatomer, eller -C0NR"2, substituert-CONR Ry hvor R er hydrogen eller alkyl med 1 - h carbonatomer, og R^ er alkyl med 1 - k carbonatomer, og dessuten en acylgruppe-COR 6 'hvor R 6ér 'alkyl med 1 - h carbonatomer eller fenyl, og salter derav med uorganiske eller organiske syrer. ;Forbindelsene av formel I og deres salter oppviser ved oral administrasjon til mus-og rotter en utpreget sentraldempénde virksomhet som f.eks. viser seg■ved-dreiestangproven. Dessuten har de en hoy kataleptisk virksomhet ved forsok på rotter. I begge retninger overtreffer de det kjente psykotrope legemiddel "Chlorpromazin". ;Et typisk eksempel på forbindelsene fremstilt ifolge oppfinnelsen ;er S-klor-lO-f^-C2-aminocarbonylethyl)-piperazino]-10,11-dihydro-dib' enzo-[b,f]-thiepin-av formel I hvor R T er klor, R Per -CONH^, ;som ble provet i form av det normale tartrat. I de folgénde tabeller er angitt de midlere virksomme resultater [ED^0i mg/kg] i dreie-stangproven på mus og i kåtalepsiforsok på rotter, for den nevnte forbindelse og for "Chlorpromazin": ; ; Av verdiene i tabellen fremgår tydelig at fremgangsmåteforbindelsen i begge forsok er vesentlig mere aktiv og derfor har gade forutsetninger for anvendelse ved behandling av sinnslidelser. Toxi-siteten av fremgangsmåteforbindelsen er bare litt hoyere enn toxi-siteten av "Chlorpromazin" [LD^q for "Chlorpromazin" for mus ved oral administrasjon er 198 mg/kg, mens den for fremgangsmåteforbindelsen er 128 mg/kg.]. ;Ifolge oppfinnelsen fremstilles de nye forbindelser av formel I ved at acrylsyrederivater av den generelle formel II: ; 2 hvor R er som ovenfor angitt, omsettes med sekundære aminer av den generelle formel: ; hvor R"<*>"er som ovenfor angitt, hvorefter eventuelt det dannede basiske produkt ved noytralisasjon med en organisk eller uorganisk syre overfores til det tilsvarende salt. : R"*" is halogen, ;R is -cyano, -C00H or -COOR^, where is alkyl with 1 - h carbon atoms, or -C0NR"2, substituted-CONR Ry where R is hydrogen or alkyl with 1 - h carbon atoms, and R^ is alkyl of 1 - k carbon atoms, and furthermore an acyl group-COR 6 'where R 6 is 'alkyl of 1 - h carbon atoms or phenyl, and salts thereof with inorganic or organic acids. ;The compounds of formula I and their salts exhibit, when administered orally to mice and rats, a pronounced central depressant activity, as is evident, for example, in the turning-rod test. Furthermore, they have a high cataleptic activity when tested on rats. In both directions, they surpass the known psychotropic drug" Chlorpromazine". A typical example of the compounds produced according to the invention is S-chloro-10-f^-C2-aminocarbonylethyl)-piperazino]-10,11-dihydro-dib'enzo-[b,f]-thiepine-av formula I where R T is chlorine, R Per -CONH^, which was tested in the form of the normal tartrate. The following tables show the average effective results r [ED^0i mg/kg] in the turning-rod test on mice and in the catalepsy test on rats, for the mentioned compound and for "Chlorpromazine": ; ; From the values in the table, it is clear that the method compound in both experiments is significantly more active and therefore has good prerequisites for use in the treatment of mental disorders. The toxicity of the method compound is only slightly higher than the toxicity of "Chlorpromazine" [LD^q of "Chlorpromazine" for mice by oral administration is 198 mg/kg, while that of the method compound is 128 mg/kg.]. According to the invention, the new compounds of formula I are prepared by acrylic acid derivatives of the general formula II: 2 where R is as stated above, is reacted with secondary amines of the general formula: ; where R"<*>" is as stated above, after which the formed basic product is optionally transferred to the corresponding salt by neutralization with an organic or inorganic acid.
Omsetningen utfores fortrinnsvis i t-butanol som reaksjons-medium ved en temperatur på 50°C og i nærvær av triethylbenzylammoniumhydroxyd som katalysator. The reaction is preferably carried out in t-butanol as reaction medium at a temperature of 50°C and in the presence of triethylbenzylammonium hydroxide as catalyst.
I det siste trinn anvendes med fordel maleinsyre til noytralisasjon av det basiske produkt. In the last step, maleic acid is advantageously used to neutralize the basic product.
Ved utforelse av■foreliggende fremgangsmåte kan som reak-sjonskomponenter av den generelle formel II foruten acrylsyren også anvendes•estere, nitrilet, amidet og substituerte amider derav, og dessuten alkylvinylketoner, henholdsvis fenylvinylketon. Addisjons-reaksjonen utfores enten med et måtelig eller betraktelig overskudd av komponentene av formel II, enten uten anvendelse av et opplbs-ningsmiddel eller i et egnet organisk opplosningsmiddel. Som et særlig vel egnet medium har ved denne type av omsetning t-butanol vist seg å være. Reaksjonen forloper tilstrekkelig raskt allerede ved noe forhbyede temperaturer (ca. 50°C) og gir sluttproduktene i godt utbytte. For å lette addisjonen tjener katalysatorer av gruppen de kvartære ammoniumhydroxyder, f.eks. triethylbenzylammoniumhydroxyd. When carrying out the present method, in addition to the acrylic acid, esters, the nitrile, the amide and substituted amides thereof, and also alkyl vinyl ketones, respectively phenyl vinyl ketone, can be used as reaction components of the general formula II. The addition reaction is carried out either with a moderate or considerable excess of the components of formula II, either without the use of a solvent or in a suitable organic solvent. For this type of reaction, t-butanol has proven to be a particularly suitable medium. The reaction proceeds sufficiently quickly already at somewhat elevated temperatures (approx. 50°C) and gives the end products in good yield. To facilitate the addition, catalysts of the quaternary ammonium hydroxide group, e.g. triethylbenzylammonium hydroxide.
De erholdte produkter av formel I er basiske av natur og gir ved noytralisasjori med' anorganiske eller organiske syrer krystallinske salter. Når man til noytralisasjonen anvender farmakodynamiske godtagbare syrer, kan de erholdte salter anvendes til terapeutiske formål. Selv i form av saltene er fremgangsmåteproduktene bare lite vannopplbselige og er derfor egnet til fremstilling av orale lege-middelformer. The obtained products of formula I are basic in nature and upon neutralization with inorganic or organic acids give crystalline salts. When pharmacodynamically acceptable acids are used for the neutralization, the salts obtained can be used for therapeutic purposes. Even in the form of the salts, the process products are only slightly water-soluble and are therefore suitable for the production of oral pharmaceutical forms.
Eksempel 1 Example 1
Til en suspensjon av 35 g 8-klor-10-piperazino-10,11-dihydrodibenzo-[b,f]-thiepin i 25.0 ml t-butanol tilsettes ved 30°C 3 ml 50%- ig methanolisk opplosning av triethylbenzylammoniumhydroxyd og til dette dryppes 11,8 g acrylonitril i 60 ml t-butanol.. Reak-sjonsblahdingen omrbres i 2 timer ved 30°C og derefter i 3 timer i et vannbad ved 50°C. Under nedsatt trykk destilleres opplbsnings-midlet av og det krystallinske residuum opplbses i 350 ml benzen. Oppløsningen rystes med 280 ml 3N saltsyre, det utskilte krystallinske hydroklorid av produktet frasuges, vaskes med vann og litt benzen. Produktet suspenderes så i 1200 ml vann,. suspensjonen gjbres alkalisk med 175 ml konsentrert vandig ammoniakk og den frigjorte base ekstraheres med benzen. Ekstraktet vaskes med vann, tbrres med vannfritt natriumsulfat og inndampes. Residuet utgjor det nesten rene, krystallinske 8-klor-10-[k--(2-cyanethyl)-piperazino]-10,11-dihydrodibenzoe-[b,f]-thiepin, som smelter ved 108-111°C. Utbyttet er 3750 g, dvs. 92%. Ved en gangs omkrystallisasjon fra ethanol får man det analytisk rene produkt med smeltepunkt 111-112°C. Efter noytralisasjon med maleinsyre i ethanol får man det krystallinske maleat med smeltepunkt 170-171°C, som kan bringes til opplosning i vann i 0,2 - 0,3$-ig konsentrasjon. To a suspension of 35 g of 8-chloro-10-piperazino-10,11-dihydrodibenzo-[b,f]-thiepine in 25.0 ml of t-butanol is added at 30°C 3 ml of a 50% methanolic solution of triethylbenzylammonium hydroxide and to 11.8 g of acrylonitrile in 60 ml of t-butanol are dropped into this. The reaction mixture is stirred for 2 hours at 30°C and then for 3 hours in a water bath at 50°C. Under reduced pressure, the solvent is distilled off and the crystalline residue is dissolved in 350 ml of benzene. The solution is shaken with 280 ml of 3N hydrochloric acid, the separated crystalline hydrochloride of the product is sucked off, washed with water and a little benzene. The product is then suspended in 1200 ml of water. the suspension is made alkaline with 175 ml of concentrated aqueous ammonia and the liberated base is extracted with benzene. The extract is washed with water, treated with anhydrous sodium sulfate and evaporated. The residue constitutes the almost pure, crystalline 8-chloro-10-[k-(2-cyanethyl)-piperazino]-10,11-dihydrodibenzoe-[b,f]-thiepine, which melts at 108-111°C. The yield is 3750 g, i.e. 92%. A single recrystallization from ethanol yields the analytically pure product with a melting point of 111-112°C. After neutralization with maleic acid in ethanol, the crystalline maleate with a melting point of 170-171°C is obtained, which can be dissolved in water in a concentration of 0.2 - 0.3%.
Eksempel 2 Example 2
I 60 ml vannfri t-butanol suspenderes 10 g 8-klor-10-piper-azino-10,ll-dihydrodibenzo-[b,f]-thiepin og der tilsettes 1 ml 50%-ig methanolisk opplosning av triethylbenzylammoniumhydroxyd, og under omrbring tildryppes en opplosning av 7,8 g acrylsyremethylester i 15 ml t-butanol. Reaksjonsblandingen omrbres i 2 timer ved 30°C og-derefter i 2 timer ved 50°C. Efter henstand over natten avdampes t-butanol under nedsatt trykk, det morke oljeaktige residuum opplbses i 100 ml benzen, opplbsningen vaskes med vann og derefter rystes med 80 ml 3N saltsyre. Det utskilte faste hydrokloridprodukt frasuges, vaskes med vann og benzen. Produktet suspenderes så i 500 ml vann, frigjbres ved alkalisering med vandig ammoniakk og isolering ved benzenekstraksjon. Ekstraktet vaskes med vann, torres med vannfritt magnesiumsulfat og inndampes. Det oljeaktige residuum utgjor nesten ren 8-klor-lO-f^-(2-methoxycarbonylethyl)-piperazino]-10,ll-dihydrodibenzo-[b,f]-thiepin. Utbytte 8,0 g. Ved henstand krystalliserer det til et fast stoff som efter en gangs krystalli-sasjon fra methanol er analytisk rent og smelter ved 100 - 101°C. Efter noytralisasjon med maleinsyre i-methanol får man det krystallinske maleat med smeltepunkt lM+-1^5°C (methanol). In 60 ml of anhydrous t-butanol, 10 g of 8-chloro-10-piper-azino-10,11-dihydrodibenzo-[b,f]-thiepine are suspended and 1 ml of a 50% methanolic solution of triethylbenzylammonium hydroxide is added, and with stirring a solution of 7.8 g of acrylic acid methyl ester in 15 ml of t-butanol is added dropwise. The reaction mixture is stirred for 2 hours at 30°C and then for 2 hours at 50°C. After standing overnight, t-butanol is evaporated under reduced pressure, the dark oily residue is dissolved in 100 ml of benzene, the solution is washed with water and then shaken with 80 ml of 3N hydrochloric acid. The separated solid hydrochloride product is suctioned off, washed with water and benzene. The product is then suspended in 500 ml of water, liberated by alkalization with aqueous ammonia and isolated by benzene extraction. The extract is washed with water, dried with anhydrous magnesium sulfate and evaporated. The oily residue is almost pure 8-chloro-10-f-(2-methoxycarbonylethyl)-piperazino]-10,11-dihydrodibenzo-[b,f]-thiepine. Yield 8.0 g. On standing, it crystallizes into a solid which, after a single crystallization from methanol, is analytically pure and melts at 100 - 101°C. After neutralization with maleic acid in methanol, the crystalline maleate is obtained with a melting point of 1M+-1^5°C (methanol).
Eksempel 3 Example 3
På samme måte som i de foregående eksempler utfores omsetningen av 10,0 g 8-klor-10-piperazino-10,ll-dihydrodibenzo-[b,f]-thiepin med 6,5 g acrylsyreamid i 80 ml t-butanol. Man får 11,^ g 8-klor-10-[^-(2-aminocarbonylethyl)-piperazino]-10,11-dihydrodi-benzo-[b,f]-thiepin med smeltepunkt 210-211°C (ethanol). Ved nby-tralisasjon med maleinsyre i vandig ethanol gir basen det tilsvarende krystallinske maleat med smeltepunkt l69-170°C (vann-ethanol). In the same way as in the previous examples, the reaction of 10.0 g of 8-chloro-10-piperazino-10,11-dihydrodibenzo-[b,f]-thiepine is carried out with 6.5 g of acrylic acid amide in 80 ml of t-butanol. 11.5 g of 8-chloro-10-[^-(2-aminocarbonylethyl)-piperazino]-10,11-dihydrodi-benzo-[b,f]-thiepine with melting point 210-211°C (ethanol) are obtained. On neutralization with maleic acid in aqueous ethanol, the base gives the corresponding crystalline maleate with a melting point of 169-170°C (water-ethanol).
Eksempel V Example V
På analogt vis som i de foregående eksempler utfores omsetningen av 8-klor-10-piperazino-10,ll-dihydrodibenzo-[b,f]-thiepin med 6,3 g methylvinylketon i 60 ml t-butanol. Man får 13,^+ g av det ikke krystalliserende, ikke helt homogene produkt, som man for rensning kromatograferer på en kolonne av 250 g aluminiumdxyd, og utvasker med benzen. Ved inndampning av benzeneluatet får man 7,6 g 8-klor-lO-^-(3-oxobutyl)-piperazino]-10,11-dihydrodibenzo-[b,f]-thiepin i ren form som smelter ved 126-128°C (ethanol). Ved noytralisasjon med maleinsyre i ethanol får man det tilsvarende krystallinske maleat med smeltepunkt 122-125°C (ethanol). In an analogous manner as in the previous examples, the reaction of 8-chloro-10-piperazino-10,11-dihydrodibenzo-[b,f]-thiepine is carried out with 6.3 g of methyl vinyl ketone in 60 ml of t-butanol. 13.^+ g of the non-crystallizing, not completely homogeneous product is obtained, which for purification is chromatographed on a column of 250 g of aluminum oxide, and washed out with benzene. Evaporation of the benzene eluate gives 7.6 g of 8-chloro-10-^-(3-oxobutyl)-piperazino]-10,11-dihydrodibenzo-[b,f]-thiepine in pure form, which melts at 126-128° C (ethanol). Neutralization with maleic acid in ethanol yields the corresponding crystalline maleate with a melting point of 122-125°C (ethanol).
Eksempel 5 Example 5
På analogt vis som beskrevet i de foregående eksempler får man ved tilsetning av acrylsyre til 8-klor-10-piperazino-10,11-dihydrodibenzo-[b,f]-thiepin 8-klor-10-[ h-(2-carboxyethyl)-piper-azino]-10,ll-dihydrodibenzo-[b,f]-thiepin med smeltepunkt 175-178°C, som utskilles fra vandig ethanol som monohydrat. Ved noytralisasjon med maleinsyre i ethanol gir basen det tilsvarende krystallinske maleat med smeltepunkt l8<l>f-l85°C (ethanol). In an analogous way as described in the preceding examples, by adding acrylic acid to 8-chloro-10-piperazino-10,11-dihydrodibenzo-[b,f]-thiepine 8-chloro-10-[ h-(2-carboxyethyl )-piper-azino]-10,11-dihydrodibenzo-[b,f]-thiepine with melting point 175-178°C, which separates from aqueous ethanol as monohydrate. Upon neutralization with maleic acid in ethanol, the base gives the corresponding crystalline maleate with a melting point of 18<l>f-185°C (ethanol).
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS710769 | 1969-10-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO129349B true NO129349B (en) | 1974-04-01 |
Family
ID=5419586
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO389070A NO129349B (en) | 1969-10-25 | 1970-10-15 |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS4843914B1 (en) |
| AT (1) | AT297006B (en) |
| BE (1) | BE757868A (en) |
| CH (1) | CH536319A (en) |
| DE (1) | DE2051972A1 (en) |
| ES (1) | ES384866A1 (en) |
| FR (1) | FR2070163B1 (en) |
| GB (1) | GB1266670A (en) |
| NL (1) | NL7015528A (en) |
| NO (1) | NO129349B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS249455B1 (en) * | 1985-01-24 | 1987-03-12 | Miroslav Protiva | N-substituted 2-chloro-7-fluoro-10-piperazino-10,11-dihydrodibenzo(b,f)thiepines and their salts and method of their preparation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL137032C (en) * | 1967-03-28 | Richardson Merrell Spa | ||
| CH491953A (en) * | 1967-05-15 | 1970-06-15 | Spofa Vereinigte Pharma Werke | Process for the preparation of tetracyclic piperazine derivatives |
| CH539044A (en) * | 1967-10-06 | 1973-08-31 | Gnii Orch Poluproduktov I Kras | Process for the preparation of quaternary ammonium salts of 1,3-bis (aminomethyl) imidazolidones |
-
0
- BE BE757868D patent/BE757868A/en unknown
-
1970
- 1970-10-15 NO NO389070A patent/NO129349B/no unknown
- 1970-10-21 CH CH1554570A patent/CH536319A/en not_active IP Right Cessation
- 1970-10-22 DE DE19702051972 patent/DE2051972A1/en active Pending
- 1970-10-23 NL NL7015528A patent/NL7015528A/xx unknown
- 1970-10-23 JP JP9339670A patent/JPS4843914B1/ja active Pending
- 1970-10-23 GB GB1266670D patent/GB1266670A/en not_active Expired
- 1970-10-23 AT AT958770A patent/AT297006B/en not_active IP Right Cessation
- 1970-10-24 ES ES384866A patent/ES384866A1/en not_active Expired
- 1970-10-26 FR FR7038624A patent/FR2070163B1/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB1266670A (en) | 1972-03-15 |
| CH536319A (en) | 1973-04-30 |
| FR2070163A1 (en) | 1971-09-10 |
| DE2051972A1 (en) | 1971-05-06 |
| ES384866A1 (en) | 1973-07-16 |
| FR2070163B1 (en) | 1975-08-01 |
| NL7015528A (en) | 1971-04-27 |
| BE757868A (en) | 1971-04-01 |
| JPS4843914B1 (en) | 1973-12-21 |
| AT297006B (en) | 1972-03-10 |
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