CS200277B1 - Method of preparing non-cataleptic neuroleptic 2-clor-10-/4-(2-hydroxyethyl)piperazino/-10,11-dihydrodibenzo(b,f)thiepine - Google Patents
Method of preparing non-cataleptic neuroleptic 2-clor-10-/4-(2-hydroxyethyl)piperazino/-10,11-dihydrodibenzo(b,f)thiepine Download PDFInfo
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- CS200277B1 CS200277B1 CS131779A CS131779A CS200277B1 CS 200277 B1 CS200277 B1 CS 200277B1 CS 131779 A CS131779 A CS 131779A CS 131779 A CS131779 A CS 131779A CS 200277 B1 CS200277 B1 CS 200277B1
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- thiepine
- piperazino
- hydroxyethyl
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- 238000000034 method Methods 0.000 title claims description 11
- 239000003176 neuroleptic agent Substances 0.000 title claims description 5
- 230000000701 neuroleptic effect Effects 0.000 title claims description 5
- 230000002903 catalepsic effect Effects 0.000 title claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 239000002585 base Substances 0.000 claims description 13
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims 2
- 238000013475 authorization Methods 0.000 claims 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- -1 4-ethoxycarbonylpiperazino Chemical group 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- LNOQURRKNJKKBU-UHFFFAOYSA-N ethyl piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNCC1 LNOQURRKNJKKBU-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- BMQLWINJIGEDEK-UHFFFAOYSA-N 2-[4-(3-chloro-5,6-dihydrobenzo[b][1]benzothiepin-6-yl)piperazin-1-yl]ethanol Chemical compound C1CN(CCO)CCN1C1C2=CC=CC=C2SC2=CC=C(Cl)C=C2C1 BMQLWINJIGEDEK-UHFFFAOYSA-N 0.000 description 1
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- LOVVGMSLLUKPKJ-UHFFFAOYSA-N 3-chlorobenzo[b][1]benzothiepine Chemical compound C1=CC2=CC(Cl)=CC=C2SC2=CC=CC=C21 LOVVGMSLLUKPKJ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002955 isolation Methods 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000001304 sample melting Methods 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Vynález se týká nového způsobu přípravy nekataleptického neuroleptika 2-chlor-lO-/4-(2-hydroxyethyl)piperazino/-10,ll-dihyčLrodibenzo (b,f) thiepinu vzorce IThe present invention relates to a novel process for the preparation of the non-cataleptic neuroleptic 2-chloro-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodrodibenzo (b, f) thiepine of formula I
Látka Vzorce I a její soli, zejména sukcinát, vykazují vlastnosti neuroleptika téměř prostého kstaleptického účinku (A.Dlabač a spol., Activ.Nerv.Super. 17. 217.1975; 2. Votava a spol., tamtéž, atr. 2l6j M. Valohář a A.Dlabač, česk.Pyeiol. 25. 277, 1976; L.G.Humber a spol., J.Med.Chem. 21, 1225, 1978). z čehož je vyvozováno, že jde o potenciální antipsychotikum se silně omezenými extrapyramidovými vedlejšími účinky.The compound of Formula I and its salts, in particular the succinate, exhibit properties of a neuroleptic almost free of crystalline activity (A.labac et al., Activ.Nerv.Super. 17, 217.1975; 2. Votava et al., Ibid., Atr. and A. Dlabac, Czech Republic, Pyeiol, 25, 277, 1976; LGHumber et al., J. Med. Chem., 21, 1225, 1978). from which it is concluded that it is a potential antipsychotic with severely limited extrapyramidal side effects.
Příprava látky vzorce I byla popsána substituční reakcí 2,10-dichlor-10,ll-dihydrodibenzo (b,f)thiepinu (K»Pelz a spol. Collect.Czech.Chem.Commun. 33. 1852, 1968) s 1-(2-hydroxyethyl)piperazinem (viz J.O.Jílek a spol., tamtéž 40. 2887, 1975). Nevýhodou této metody je, že poskytuje jen 65 % výtěžek ne žádané látce vzorce I; jako významná vedlejší reakoe se uplatňuje eliminace, jejímž produktem je nežádoucí 2-chlordibenzo(b,f)thiepin.The preparation of the compound of formula I has been described by substitution reaction of 2,10-dichloro-10,11-dihydrodibenzo (b, f) thiepine (K K Pelz et al. Collect.Czech.Chem.Commun. 33. 1852, 1968) with 1- ( 2-hydroxyethyl) piperazine (see JOJílek et al., Ibid. 40, 2887, 1975). The disadvantage of this method is that it provides only a 65% yield on the desired compound of Formula I; A significant side reaction is elimination, the product of which is the undesirable 2-chlorodibenzo (b, f) thiepine.
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Nyní bylo zjištěno, že látku vzorce I lze připravit hydroxyethylaci 2-chlor-lO-piperazlno-10,ll-dihydrodibenzo (b,f) thiepinu vzorce 11It has now been found that the compound of formula I can be prepared by hydroxyethylation of 2-chloro-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine of formula 11
ClCl
Tento nový způsob přípravy laťky vzorce I je předmětem vynálezu. K hydroxyethylaci lze použít buď působení ethylenoxidu nebo 2-chlorethanolu; obě tyto modifikace hydroxyethylaění reakce jsou zahrnuty v předmětu tohoto vynálezu. Reakci báze vzorce 11 e ethylenoxidem lze provést při teplotách 0 až 50 °C v různých rozpouštědlech. S výhodou lze použít nižších alkoholů, zejména methanolu nebo ethanolu. Do míchaného roztoku báze vzorce II v uvedeném rozpouštědle se zvolna uvede přx vhodná teplotě (optimum při 35 až 40 °C) nejméně 100% přebytek plynného ethylenoxidu. Adice ethylenoxidu na sekundární aminovou skupinu báze vzorce II probíhá rychle a vzniklý produkt vzorce I se snadno izoluje na základě bazického charakteru. Fři použiti uvedeného přebytku ethylenoxidu nezůstává v reakční směsi žádná nezreagovaná výchozí látka vzorce II, což izolaci produktu vzorce I v čistém stavu usnadňuje.This novel process for preparing the bar of formula I is an object of the invention. Either ethylene oxide or 2-chloroethanol can be used for hydroxyethylation; both of these modifications of the hydroxyethylation reaction are included within the scope of the present invention. The reaction of the base of formula 11e with ethylene oxide can be carried out at temperatures of 0 to 50 ° C in various solvents. Lower alcohols, in particular methanol or ethanol, may preferably be used. At least 100% excess ethylene oxide gas is slowly introduced into a stirred solution of the base of formula II in said solvent at a suitable temperature (optimum at 35-40 ° C). The addition of ethylene oxide to the secondary amine group of the base of formula II proceeds rapidly and the resulting product of formula I is readily isolated on the basis of basic nature. By using this excess ethylene oxide, no unreacted starting material of formula II remains in the reaction mixture, which facilitates the isolation of the product of formula I in a pure state.
Druhý způsob hydroxyethylaění reakce spočívá v alkylsci báze vzorce II 2-chlorethanolem. Také tuto reakci lze provést v různých rozpouštědlech, přičemž zvláště výhodné jsou ethanol nebo aceton. Reakce probíhá hladce při teplotáoh 50 až 100 °C a za přítomnosti bezvodého alkalického uhličitanu jako kondenzačního činidla. Fři práoi v ethanolu se pracuje s výhodou při 70 °C. Také v tomto případě se báze vzorce 1 izoluje na základě svého zásaditého charakteru.A second method of hydroxyethylation of the reaction consists in the alkyl of the base of formula II with 2-chloroethanol. This reaction can also be carried out in various solvents, ethanol or acetone being particularly preferred. The reaction proceeds smoothly at 50 to 100 ° C and in the presence of anhydrous alkali carbonate as condensing agent. Preferably, the ethanol is worked at 70 ° C. In this case too, the base of formula 1 is isolated on the basis of its basic character.
Výchozí látka vzorce II nebyla zatím v literatuře popsána a proto je její způsob přípravy zahrnut do příkladu provedení. Lze ji získat nejlépe dvoustupňovým pochodem, při kterém se nejříve provede substituční reakce 2,10-dichlor-10,ll-dihydrodibenzo (b,f) thiepinu s l-(ethoxykarbonyl)piperazinem. Tato substituční reakce probíhá s vysokým výtěžkem a eliminace se při ní uplatňuje maximálně z 10 %. Reaultuje 2-chlor-lO-(4-ethoxykarbonylpiperazino)-10,ll-dihydro-dibenzo(b,f)thiepin, který se v druhém stupni alkalicky hydrolizuje. Také tento stupeň poskytuje vysoký, téměř teoretický výtěžek, což činí celý postup teohnioky výhodným.The starting material of formula (II) has not been described in the literature so far and its preparation method is included in the exemplary embodiment. It is best obtained by a two-step process, in which the substitution reaction of 2,10-dichloro-10,11-dihydrodibenzo (b, f) thiepine with 1- (ethoxycarbonyl) piperazine is first carried out. This substitution reaction proceeds with a high yield and elimination takes place to a maximum of 10%. This results in 2-chloro-10- (4-ethoxycarbonylpiperazino) -10,11-dihydro-dibenzo (b, f) thiepine, which is alkalinized in the second step. This step also provides a high, almost theoretical yield, which makes the entire Teohnio process advantageous.
Konečný produkt podle vynálezu, tj. báze vzorce I, je krystalickou látkou, která Výborně krystaluje z acetonu a v čistém stavu taje při 102 až 103 °C. Neutřellsaoí kyselinou jantarovou poskytuje krystalický sukelnát, který krystaluje z ethanolu a v čistém stavu taje při 166 až 168 °C.The end product of the invention, i.e. the base of formula I, is a crystalline substance which crystallizes excellently from acetone and melts in the pure state at 102-103 ° C. Neutral salt with succinic acid provides a crystalline succinate which crystallizes from ethanol and melts in the pure state at 166-168 ° C.
Příklady provedeníExamples
1. Do míchaného roztoku 19 g 2-chlor-10-piperazino-10,ll-dihydrodibenzo(b,f)thiepinu ve 200 ml methanolu se při teplotě 36 až 40 °C během 3 hodin uvede 8,8 g plynného ethylenoxidu. Směs se ponechá v klidu přes noc, methanol se odpaří za sníženého tlaku, zbytek se rozpustí' ve 100 ml chloroformu a produkt se z tohoto roztoku extrahuje třepáním do nejméně1. To a stirred solution of 2-chloro-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine (19g) in methanol (200ml) was added ethylene oxide gas (8.8g) at 36-40 ° C for 3 hours. The mixture is left overnight, the methanol is evaporated off under reduced pressure, the residue is dissolved in 100 ml of chloroform and the product is extracted from this solution by shaking to at least
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30% přebytku žlí-HgSO^. Kyselý vodný roztok se oddělí, zfiltruje se s aktivním uhlím a filtrát se zalkallzuje hydroxidem amonným. Uvolněná báze se extrahuje chloroformem,extrakt se suší uhličitanem draselným a odpaří. Získá se 14,0 g (75 %) olejovitého 2-chlor-lO-/4-(2-hydroxyethyl)piperazino/-10,ll-dihydrodibenzo(b,f)-thiepinu (I), který stáním zvolna krystaluje a jehož vzorek po rekrystalisaoi z acetonu taje při 102 až 103 °C. Neutralizací kyselinou jantarovou v ethanolu poskytuje krystalický sukcinát., jehož vzorek po rekrystalizaci z ethanolu taje při 166 až 168 °C.30% excess of H 2 SO 4. The acidic aqueous solution was separated, filtered with charcoal and the filtrate basified with ammonium hydroxide. The liberated base was extracted with chloroform, the extract was dried with potassium carbonate and evaporated. 14.0 g (75%) of oily 2-chloro-10- (4- (2-hydroxyethyl) piperazino) -10,11-dihydrodibenzo (b, f) -thiepine (I) are obtained, which crystallizes slowly on standing and in which the sample melts at 102-103 ° C after recrystallization from acetone. Neutralization with succinic acid in ethanol gives a crystalline succinate, the sample of which melts at 166-168 ° C after recrystallization from ethanol.
Výchozí 2-chlor-10-piperazino-10Tll-dihydrodibenzo(b,f) thiepin (II), jehož příprava zatím nebyla v literatuře popsána, se získá nejlépe dále uvedeným postupem ze známéhoThe starting 2-chloro-10-piperazino-10 T ll-dihydro-dibenzo (b, f) thiepin (II), whose preparation has not yet been described in literature, is obtained preferably by the following procedure from the known
2,10-dichlor-10,ll-dihydrodibenzo(b,f)thiepinu (K.Pelz a spol., literatura citována):2,10-dichloro-10,11-dihydrodibenzo (b, f) thiepine (K.Pelz et al., References cited):
Směs 13,3 g 2,10-dichlor-10,ll-dihydrodibenzo(b,f)thiepinu, 24 g 1-(ethoxykarbonyl) piperazinu a 24 ml chloroformu se míchá a vaří 5 hodin pod zpětným chladičem, ^otom ae zředí 150 ml benzenu, promyje ae vodou a bazický produkt se extrahuje třepáním a přebytečnou 2U-R2S0^. Oddělený kyselý vodný roztok, ze kterého ae vylučuje pevný sulfát, sa zalkáli zuje hydroxidem amonným a uvolněná báze se extrahuje benzenem. Extrakt ae vysuší uhličitanem draselným a odpaří za sníženého tlaku. Získá se 17,1 g (90 %) surového olejovitého 2-chlor-10-(4-ethoxykarbonylpiperazino)-10,ll-dibydrodibenzo(b,f)thiepinu. K jeho charakte rizaci se hodí neutralizace kyselinou maleinovou v ethanolu; přídavkem etheru k vzniklému roztoku soli se vyloučí krystalický hydrogenmaleinát, jehož vzorek po krystalizaci z ethanolu taje při 142 až 144 °C.A mixture of 13.3 g of 2,10-dichloro-10,11-dihydrodibenzo (b, f) thiepine, 24 g of 1- (ethoxycarbonyl) piperazine and 24 ml of chloroform is stirred and refluxed for 5 hours, then diluted with 150 ml. ml of benzene, washed with water, and e the basic product is extracted by shaking and excess 2U-R-S0 2. The separated acidic aqueous solution from which a solid sulfate is precipitated is basified with ammonium hydroxide and the liberated base is extracted with benzene. The extract was dried over potassium carbonate and evaporated under reduced pressure. 17.1 g (90%) of crude oily 2-chloro-10- (4-ethoxycarbonylpiperazino) -10,11-dibydrodibenzo (b, f) thiepine are obtained. Neutralization with maleic acid in ethanol is suitable for its characterization; addition of ether to the resulting salt solution precipitated crystalline hydrogen maleate, the sample melting at 142-144 ° C after crystallization from ethanol.
Směs 17,0 g předešlé olejovité baze, 25 g hydroxidu draselného a 30 ml ethanolu aa míchá a vaří 3 hodiny pod zpětným ohladičem. Potom ae zředí 150 ml vody a extrahuje sa chloroformem. Vysušením a odpařením extraktu ae získá 13,1 g (93 %) surové baze 2-chlor-10-piperazino-10,ll-dihydrodlbenzo(b,f) thiepinu a t.t. 120 až 126 °C. Jedinou krystalizací z oyklohexanu ae získá čistá látka s t.t. 126 až 126 °C. K charakterizaci je vhodný dimethansulfonát, který ae získá neutralizaci baze kyselinou methasulfónovou a který krystaluje z vodného ethanolu jako hemihydrát, t.t. 209 až 210 °C,A mixture of 17.0 g of the previous oily base, 25 g of potassium hydroxide and 30 ml of ethanol and was stirred and refluxed for 3 hours. It is then diluted with 150 ml of water and extracted with chloroform. Drying and evaporation of the extract yielded 13.1 g (93%) of the crude base of 2-chloro-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine and mp 120-126 ° C. A single crystallization from oyclohexane yields the pure product, mp 126-126 ° C. For characterization, a dimethanesulfonate is obtained which is obtained by neutralizing the base with methasulfonic acid and which crystallizes from aqueous ethanol as the hemihydrate, mp 209-210 ° C,
2. K míchané směsi 19,3 g 2-chlor-10-piperazino-10,ll-dihydrodibenzo (b,f) thiepinu, 100 ml ethanolu a 16,8 g bezvodého uhličitanu draselného se při 70 °C přikape během 30 minut roztok 8,1 g 2-chlor-ethaholu v 10 ml ethanolu. Směs se míchá 5 hodin při 70 °0, potom se ochladí, zfiltruje a filtrát se za sníženého tlaku odpaří. Zbytek se rozpustí ve 1Q0 ml chloroformu,roztok se promyje vodou a bázieký produkt se extrahuje třepáním do přebytečné 2M-H2SO4. Získaný kyselý vodný roztok se oddělí, zfiltruje se s aktivním uhlím a filtrát se alkalizuje hydroxidem draselným, b^ze ae opět extrahuje chloroformem, extrakt ae vysuší uhličitanem draselným a odpaří* Získá ae 15,0 g (60 olejovitého 2-chlor-10-/4-(2-hydroxyethyl)piperazino/-10,ll-dihydrodibenzo(b,f)thiepinu (I), který stáním zvolna krystaluje. Vzorek po rekrystalizaci z acetonu taje při 102 až 103 °C. Neutralizací kyselí nou jantarovou v ethanolu poskytuje krystalický sukcinát, jehož vzorek po rekrystalizaci z ethanolu taje při 166 až 168 °C.2. To a stirred mixture of 2-chloro-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine (19.3 g), ethanol (100 ml) and anhydrous potassium carbonate (16.8 g) was added dropwise at 70 ° C over 30 minutes. 8.1 g of 2-chloro-ethanol in 10 ml of ethanol. The mixture was stirred at 70 ° C for 5 hours, then cooled, filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in 10 ml of chloroform, the solution was washed with water and the basic product was extracted by shaking into excess 2M-H 2 SO 4. The acidic aqueous solution obtained was separated, filtered with charcoal and the filtrate basified with potassium hydroxide, extracted again with chloroform, extracted and dried with potassium carbonate and evaporated to give 15.0 g (60 oily 2-chloro-10-). (4- (2-hydroxyethyl) piperazino) -10,11-dihydrodibenzo (b, f) thiepine (I), which slowly crystallizes on standing The sample melts at 102-103 ° C after recrystallization from acetone. yields a crystalline succinate which melts at 166-168 ° C after recrystallization from ethanol.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS131779A CS200277B1 (en) | 1979-02-27 | 1979-02-27 | Method of preparing non-cataleptic neuroleptic 2-clor-10-/4-(2-hydroxyethyl)piperazino/-10,11-dihydrodibenzo(b,f)thiepine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS131779A CS200277B1 (en) | 1979-02-27 | 1979-02-27 | Method of preparing non-cataleptic neuroleptic 2-clor-10-/4-(2-hydroxyethyl)piperazino/-10,11-dihydrodibenzo(b,f)thiepine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS200277B1 true CS200277B1 (en) | 1980-09-15 |
Family
ID=5347246
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS131779A CS200277B1 (en) | 1979-02-27 | 1979-02-27 | Method of preparing non-cataleptic neuroleptic 2-clor-10-/4-(2-hydroxyethyl)piperazino/-10,11-dihydrodibenzo(b,f)thiepine |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS200277B1 (en) |
-
1979
- 1979-02-27 CS CS131779A patent/CS200277B1/en unknown
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