CS265750B1 - Process for preparing 11-/1-/2-/1-piperazinyl/-4-piperidyliden/6,11-dihydrodibenzo/b,e/thiepines and maleinates them - Google Patents
Process for preparing 11-/1-/2-/1-piperazinyl/-4-piperidyliden/6,11-dihydrodibenzo/b,e/thiepines and maleinates them Download PDFInfo
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- CS265750B1 CS265750B1 CS885294A CS529488A CS265750B1 CS 265750 B1 CS265750 B1 CS 265750B1 CS 885294 A CS885294 A CS 885294A CS 529488 A CS529488 A CS 529488A CS 265750 B1 CS265750 B1 CS 265750B1
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- Prior art keywords
- dihydrodibenzo
- piperidylidene
- piperazinyl
- thiepine
- ethanol
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- 150000003551 thiepines Chemical class 0.000 title claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 title 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 39
- -1 1- (2- (1-piperazinyl) acetyl) -4-piperidylidene Chemical group 0.000 claims abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000009835 boiling Methods 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011976 maleic acid Substances 0.000 claims abstract description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- 150000001412 amines Chemical class 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims description 5
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 2
- 150000004885 piperazines Chemical class 0.000 claims description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003288 anthiarrhythmic effect Effects 0.000 abstract description 3
- 230000000767 anti-ulcer Effects 0.000 abstract description 3
- 239000003416 antiarrhythmic agent Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- LWEOFVINMVZGAS-UHFFFAOYSA-N 3-piperazin-1-ylpropan-1-ol Chemical compound OCCCN1CCNCC1 LWEOFVINMVZGAS-UHFFFAOYSA-N 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003444 anaesthetic effect Effects 0.000 abstract 1
- 239000013067 intermediate product Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000003595 spectral effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- STSAIUCZKQGPNG-UHFFFAOYSA-N 2-piperazin-1-ylpropan-1-ol Chemical compound OCC(C)N1CCNCC1 STSAIUCZKQGPNG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Řešení spadá do oboru syntetických léčiv. Jeho předmětem je způsob přípravy 11-(1-(2-(1-pipérazinyl)acetyl)-4-piperidyliden) -6 , 11-dihydrodibenzo/b,e/thiepinů (I) a jejich maleinátů. Látky I jsou jednak meziprodukty, jednak samy o sobě vykazují, jisté lokálně anestetické, antiarytmické a protivředové účinky. Způsob jejich přípravy spočívá ve dvoustupňovém procesu, ve kterém se předně 11-(4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepin podrobí působení chloracetylchloridu, s výhodou ve vroucím benzenu za přítomnosti Ν,Ν-dimethylacetamidu, vzniklý 11-(1-(2-chloracetyl)-4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepin se zpracuje substitučními reakcemi s 1- -methylpiperazinem, 2-(1-piperazinyl)- ethanolem a 3- (1-píperazínyl)^propanolem, provedenými s výhodou za použití 100 až 110% přebytku těchto aminů ve vroucím chloroformu a získané base I se neutralizují kyselinou maleinovou v ethanolu.The solution is in the synthetic field drugs. His subject is a method of preparation 11- (1- (2- (1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydrodibenzo / b, e / thiepines (I) and their maleates. Substances I are both intermediate products, on the one hand, certain locally anesthetic, antiarrhythmic and anti-ulcer effects. Method of their preparation lies in the two-step process in which firstly 11- (4-piperidylidene) -6,11-dihydrodibenzo / b, e / thiepine treated with chloroacetyl chloride, preferably in boiling benzene in the presence of Ν, Ν-dimethylacetamide, resulting 11- (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine by substitution reactions with 1- -methylpiperazine, 2- (1-piperazinyl) - with ethanol and 3- (1-piperazinyl) propanol, preferably carried out using 100 to 110% excess of these amines in boiling chloroform and the base I obtained are neutralized maleic acid in ethanol.
Description
(57) Řešení spadá do oboru syntetických léčiv. Jeho předmětem je způsob přípravy 11-(1-(2-(1-pipérazinyl)acetyl)-4-piperidyliden) -6 , 11-dihydrodibenzo/b,e/thiepinů (I) a jejich maleinátů. Látky I jsou jednak meziprodukty, jednak samy o sobě vykazují, jisté lokálně anestetické, antiarytmické a protivředové účinky. Způsob jejich přípravy spočívá ve dvoustupňovém procesu, ve kterém se předně 11-(4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepin podrobí působení chloracetylchloridu, s výhodou ve vroucím benzenu za přítomnosti Ν,Ν-dimethylacetamidu, vzniklý 11-(1-(2-chloracetyl)-4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepin se zpracuje substitučními reakcemi s 1-methylpiperazinem, 2-(1-piperazinyl)ethanolem a 3- (1-píperazínyl)^propanolem, provedenými s výhodou za použití 100 až 110% přebytku těchto aminů ve vroucím chloroformu a získané base I se neutralizují kyselinou maleinovou v ethanolu.(57) The solution falls within the field of synthetic drugs. It is directed to a process for the preparation of 11- (1- (2- (1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepines (I) and their maleates. Compounds I are on the one hand intermediates, and on the other hand, exhibit certain local anesthetic, antiarrhythmic and antiulcer effects. The process for their preparation consists in a two-step process in which the 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine is first treated with chloroacetyl chloride, preferably in boiling benzene in the presence of Ν, Ν-dimethylacetamide, - (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine was treated by substitution reactions with 1-methylpiperazine, 2- (1-piperazinyl) ethanol and 3- (1-piperazinyl) 1-propanol, preferably using a 100-110% excess of these amines in boiling chloroform and the base I obtained are neutralized with maleic acid in ethanol.
Vynález se týká způsobu přípravy 11-(1-(2-(1-piperazinyl)acetyl)-4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepinů obecného vzorce IThe present invention relates to a process for the preparation of 11- (1- (2- (1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepines of the formula I
ve kterém R značí methyl, 2-hydroxyethyl nebo 3-hydroxypropyl, jakož 1 jejich maleinátů.wherein R is methyl, 2-hydroxyethyl or 3-hydroxypropyl, as well as 1 maleate thereof.
Látky obecného vzorce i podle vynálezu jsou jednak meziprodukty syntézy léčiv, jednak samy o sobě mají lokálně anestetickou, antiarytmickou a protivředovou účinnost.The compounds of the formula I according to the invention are, on the one hand, intermediates in the synthesis of medicaments and, on the other hand, have local anesthetic, antiarrhythmic and antiulcer activity on their own.
Způsob přípravy látek obecného vzorce I podle vynálezu spočívá ve dvoustupňovém procesu, při kterém se vychází z 11-(4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepinu, který se v prvním stupni podrobí působení chloracetylchloridu, s výhodou ve vroucím benzenu za přítomnosti Ν,Ν-dimethylacetamidu. Získá se krystalický ll-(l~(2-chloracetyl)-4-piperidyliden)-6,11-dihydrodíbenzo/b,e/thiepin, který se ve druhém stupni zpracuje substitučními reakcemi s 1-methylpiperazineni, 2-(1-piperazinyl)ethanolem a 2-(1-piperazinyl)propanolem (T. Zawisza a spol., Acta Pol. Pharm. 22, 477, 1965). Tyto substituční reakce lze provést za různých podmínek; s výhodou se provedou za použití 100 až 110% přebytku jmenovaných piperazinových derivátů ve vroucím chloroformu. Resultující váze obecného vzorce I jsou většinou olejovité a lze je přečistit krystalizací solí, s výhodou solí s kyselinou maleinovou, získaný neutralizací surových bází touto kyselinou v ethanolu. Příprava těchto solí, které jsou výhodnější než báze pro provádění farmakologických testů i pro přípravu lékových forem je rovněž součástí tohoto vynálezu. Výchozí 11-(4-piperídyliden)-6,11-dihydrodibenzo/b,e/thiepin zatím nebyl v literatuře popsán. Jeho syntéza ze známého 11-(l-methyl-4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepinu je popsána v příkladu 1. Další podrobnosti provedení způsobu přípravy látek obecného vzorce I podle tohoto vynálezu jsou uvedeny v příkladech, které jsou však jen ilustrací možností vynálezu. Popisované látky obecného vzorce I i meziprodukty jsou nové; jejich identita byla zajištěna analytickými i spektrálními metodami.The process for the preparation of the compounds of the formula I according to the invention consists of a two-stage process starting from 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, which is first treated with chloroacetyl chloride, preferably in boiling benzene in the presence of Ν, Ν-dimethylacetamide. There was obtained crystalline 11- (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, which was treated in the second step by substitution reactions with 1-methylpiperazinene, 2- (1-piperazinyl) ethanol and 2- (1-piperazinyl) propanol (T. Zawisza et al., Acta Pol. Pharm. 22, 477, 1965). These substitution reactions can be performed under various conditions; preferably, they are carried out using a 100-110% excess of said piperazine derivatives in boiling chloroform. The resulting weights of formula I are generally oily and can be purified by crystallization of salts, preferably maleic acid salts, obtained by neutralizing the crude bases with ethanol in ethanol. The preparation of these salts, which are more advantageous than bases for carrying out pharmacological tests and for preparing dosage forms, is also part of the present invention. The starting 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine has not been described in the literature yet. Its synthesis from the known 11- (1-methyl-4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine is described in Example 1. Further details of the process for the preparation of the compounds of formula I according to the invention are given in the Examples. but which are merely illustrative of the possibilities of the invention. The compounds of formula (I) and intermediates described are novel; their identity was assured by analytical and spectral methods.
Příklad 1Example 1
11-(1-(2-(4-methyl-1-piperazinyl)acetyl)-4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepin (I, R = CH3)11- (1- (2- (4-methyl-1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydro-dibenzo / b, e / thiepin (I, R = CH3)
K roztoku 1,50 g 11-(4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepinu a 0,62 g N,N-dimethylacetamidu ve 20 ml benzenu se za míchání přidá roztok 0,81 g chloracetylchloridu ve 20 ml benzenu a směs se vaří 1,5 h pod zpětným chladičem. Po ochlazení se zředí 60 ml chloroformu, promyje se důkladně vodou, vysuší se bezvodým síranem hořečnatým a odpaří se za sníženého tlaku. Olejovitý odparek (1,9 g) zvolna krystalizuje z benzenu. Takto se získá 1,51 g (80 %)To a solution of 1.50 g of 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine and 0.62 g of N, N-dimethylacetamide in 20 ml of benzene is added with stirring a solution of 0.81 g of chloroacetyl chloride in 20 ml of benzene and the mixture was refluxed for 1.5 h. After cooling, it is diluted with 60 ml of chloroform, washed thoroughly with water, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The oily residue (1.9 g) slowly crystallized from benzene. Thus, 1.51 g (80%) are obtained.
11-(1-(2-chloracetyl)-4-piperidyliden)-6,11-dihydrodíbenzo(b,e/thiepinu, t.t. 145 až 147 °C.11- (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrobenzo (b, e / thiepine, m.p. 145-147 ° C).
K roztoku 2,50 g předešlého chloracetylderivátu ve 40 ml chloroformu se přidá 1,5 g 1-methylpiperazinu a směs se za míchání vaří pod zpětným chladičem 2,5 h. Zředí se 60 ml chloroformu, promyje se vodou, vysuší se bezvodým uhličitanem draselným a odpaří za sníženého tlaku. Zbytek krystalizuje z benzenu a poskytne 2,42 g žádané báze, t.t. 152 až 155 C. Neutralizací kyselinou maleinovou v ethanolu se získá krystalický bis(hydrogenmaleinát), který krystalizuje z vodného ethanolu a taje při 161 až 164 C.To a solution of 2.50 g of the preceding chloroacetyl derivative in 40 ml of chloroform was added 1.5 g of 1-methylpiperazine and the mixture was heated under reflux for 2.5 h. Dilute with 60 ml of chloroform, wash with water, dry over anhydrous potassium carbonate and evaporated under reduced pressure. The residue crystallizes from benzene to give 2.42 g of the desired base, m.p. Neutralization with maleic acid in ethanol gives a crystalline bis (hydrogen maleate) which crystallizes from aqueous ethanol and melts at 161-164 ° C.
Použitý výchozí 11-(4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepin, který je látkou novou, se připraví dvoustupňovým pochodem ze známého 11-(l-methyl-4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepinu (Adlerová E. a spol., Česk. Farm. 12, 122, 1963) jak je dále uvedeno:The starting 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, which is a novel substance, is prepared by a two-step process from the known 11- (1-methyl-4-piperidylidene) -6,11-dihydrodibenzo (b, e) thiepine (Adlerova E. et al., Cesk. Farm. 12, 122, 1963) as follows:
K roztoku 5,00 q 11-(l-methyl-4-piperidyliden)-6,11-dihydrodibenzo/b, e/thiepinu (lit.To a solution of 5.00 q of 11- (1-methyl-4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine (lit.
< i t < >v.í »1.1 ί v .’*» ml ]>'-117.(-1111 ·» ,·.. i mfch.ínf |»i i dá loztok I, 53 q ch lot lina Vončanu ethylnatého v 35 ml benzenu a směs se vaří 2,5 h pod zpětným chladičem. Po ochlazení se promyje zředěnou kyselinou chlorovodíkovou a vodou, vysuší se bezvodým uhličitanem draselným a odpaří se za sníženého tlaku. Získá se 6,04 g surového olejovitého produktu, který se rozpustí v 25 ml benzenu a roztok se zfiltruje přes kolonu 15 g silikagelu. Kolona se promyje 400 ml benzenu a filtrát se odpaří. Získá se 5,05 g (85 %) téměř homogenního, olejovitého 11-(1-ethoxykarbonyl-4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepinu, jehož analytická a spektrální charakterizace potvrzuje jeho identitu.<it <> v.í »1.1 ί v '*» ml]>' - 117. (- 1111 · i, m / min) gives a solution of 53 g of ethyl acetate in ethyl acetate 35 ml of benzene and refluxed for 2.5 h, cooled, washed with dilute hydrochloric acid and water, dried over anhydrous potassium carbonate and evaporated under reduced pressure to give 6.04 g of crude oil which was dissolved. in 25 ml of benzene and the solution was filtered through a column of 15 g of silica gel, the column was washed with 400 ml of benzene and the filtrate was evaporated to give 5.05 g (85%) of an almost homogeneous, oily 11- (1-ethoxycarbonyl-4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, whose analytical and spectral characterization confirms its identity.
Směs 4,47 g předešlého ethoxykarbonylderivátu, 3,43 g hydroxidu draselného a 30 ml ethanolu se míchá a vaří 2 h pod zpětným chladičem. Po částečném ochlazení se směs zředí 50 ml vody a extrahuje se benzenem. Zpracováním extraktu se získá 2,58 g (72 %) 11-(4-piperidyliden) -6 , 1 1-dihydrodibenzo/b , e/thiepinu , který krystalizuje ze směsi benzenu a etheru a taje při 91 až 94 °C.A mixture of 4.47 g of the above ethoxycarbonyl derivative, 3.43 g of potassium hydroxide and 30 ml of ethanol is stirred and refluxed for 2 hours. After partial cooling, the mixture was diluted with 50 ml of water and extracted with benzene. Work-up of the extract gave 2.58 g (72%) of 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, which crystallized from a mixture of benzene and ether and melted at 91-94 ° C.
Příklad 2Example 2
11-(1-(2-(4-(2-hydroxyethyl)-1-piperazinyl)acetyl)-4-piperidyliden)-6,11-dihydrodibenzo/b,e/thiepin (I, R ~ CH?CH2OH)11- (1- (2- (4- ( 2- hydroxyethyl) -1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydro-dibenzo / b, e / thiepin (I, R-CH? CH 2 OH )
Podobně jako v příkladu 1 se provede reakce 2,50 g 11-(1-(2-chloracetyl)-4-piperidyliden) -6,11-dihydrodibenzo/b,e/thiepinu (viz příklad 1) s 1,94 g 2-(1-piperazinyl)ethanolu ve 40 ml chloroformu za varu pod zpětným chladičem (3 h) . Obdobným zpracováním se získá 3,10 g surové, olejovité báze, která se neutralizací kyselinou maleinovou v ethanolu převede na krystalický bis(hydrogenmaleinát) (4,20 g, 89 %), t.t. 151 až 154 °C. Rozkladem vzorku této soli vodným amoniakem, extrakcí etherem a odpařením extraktu se získá homogenní, olejovitá báze, kterou lze charakterizovat analytickými i spektrálními metodami.Similar to Example 1, 2.50 g of 11- (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine (see Example 1) is reacted with 1.94 g 2 - (1-piperazinyl) ethanol in 40 ml of chloroform at reflux (3 h). Similar work-up gave 3.10 g of crude, oily base which was converted to crystalline bis (hydrogen maleate) (4.20 g, 89%) by neutralization with maleic acid in ethanol (m.p. Mp 151-154 ° C. Decomposition of a sample of this salt with aqueous ammonia, extraction with ether and evaporation of the extract yields a homogeneous, oily base which can be characterized by analytical and spectral methods.
Příklad 3Example 3
1.1-(.1-(2- (4-(3-hydroxypropyl) -1-piperazinyl) acetyl) -4-piperidyliden) -6,11-dihydrodibenzo/b,e/thiepin (1, R - CH2CÍI2CH2OH)1.1 - (. 1- (2- (4- (3-hydroxypropyl) -1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydro-dibenzo / b, e / thiepin (1 R - CH 2 CH 2 CH 2 OH)
Podobně jako v příkladu 1 se provede reakce 2,40 g 11-(1-(2-chloracetyl)-4-piperidyliden) -6,11-dihydrodibenzo/b,e/thiepinu (viz příklad 1) s 2,06 g 3-(1-piperazinyl)propanolu (lit. citována) ve 40 ml vroucího chloroformu. Podobné zpracování poskytne 3,1 g surové, olejovité báze, která se převede neutralizací kyselinou maleinovou v ethanolu na krystalický bis(hydrogen maleinát), t.t. 110 až 113 °C (ethanol). Jako v předešlých případech se z této soli uvolní homogenní, olejovitá báze, vhodná k charakterizaci analytickými i spektrálními metodami.Similar to Example 1, the reaction of 2.40 g of 11- (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine (see Example 1) with 2.06 g of 3 is carried out. - (1-piperazinyl) propanol (lit. quoted) in 40 ml boiling chloroform. Similar work-up gave 3.1 g of crude, oily base which was converted by neutralization with maleic acid in ethanol to give crystalline bis (hydrogen maleate), m.p. 110 DEG-113 DEG C. (ethanol). As in the previous cases, a homogeneous, oily base suitable for characterization by both analytical and spectral methods is released from this salt.
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS885294A CS265750B1 (en) | 1988-07-25 | 1988-07-25 | Process for preparing 11-/1-/2-/1-piperazinyl/-4-piperidyliden/6,11-dihydrodibenzo/b,e/thiepines and maleinates them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS885294A CS265750B1 (en) | 1988-07-25 | 1988-07-25 | Process for preparing 11-/1-/2-/1-piperazinyl/-4-piperidyliden/6,11-dihydrodibenzo/b,e/thiepines and maleinates them |
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| Publication Number | Publication Date |
|---|---|
| CS529488A1 CS529488A1 (en) | 1989-02-10 |
| CS265750B1 true CS265750B1 (en) | 1989-11-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| CS885294A CS265750B1 (en) | 1988-07-25 | 1988-07-25 | Process for preparing 11-/1-/2-/1-piperazinyl/-4-piperidyliden/6,11-dihydrodibenzo/b,e/thiepines and maleinates them |
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| Country | Link |
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| CS (1) | CS265750B1 (en) |
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1988
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| Publication number | Publication date |
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| CS529488A1 (en) | 1989-02-10 |
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