CS256228B1 - Method of new fluorinated 10-piperazino-10,11-dihydrodibenzo(b,f)-thiepine preparation - Google Patents
Method of new fluorinated 10-piperazino-10,11-dihydrodibenzo(b,f)-thiepine preparation Download PDFInfo
- Publication number
- CS256228B1 CS256228B1 CS868290A CS829086A CS256228B1 CS 256228 B1 CS256228 B1 CS 256228B1 CS 868290 A CS868290 A CS 868290A CS 829086 A CS829086 A CS 829086A CS 256228 B1 CS256228 B1 CS 256228B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- dihydrodibenzo
- thiepine
- preparation
- piperazino
- propionamide
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 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 title 1
- VVWMANLRLRFZIZ-UHFFFAOYSA-N 3-piperazin-1-ylpropanamide Chemical compound NC(=O)CCN1CCNCC1 VVWMANLRLRFZIZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- TYOPPAUWUDNREA-UHFFFAOYSA-N n-piperazin-1-ylpropanamide Chemical compound CCC(=O)NN1CCNCC1 TYOPPAUWUDNREA-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 239000003176 neuroleptic agent Substances 0.000 abstract description 2
- 230000000701 neuroleptic effect Effects 0.000 abstract description 2
- 201000000980 schizophrenia Diseases 0.000 abstract description 2
- -1 3- (4- (7-Fluoro-2-isopropyl-10,11-dihydrodibenzo (b, f) thiepin-11-yl) -1-piperazinyl) - propionamide Chemical compound 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 230000007774 longterm Effects 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 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
- 239000000155 melt Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Řešení spadá do oboru synthetických léčiv. Jeho předmětem je způsob přípravy nového fluorovaného 10-piperazino-10,11- -dihydrodibenzo(b,f)thiepinu vzorce I (I) , t j . 3- (4- (7-fluor-2-isopropy1-10,11-dihydrodibenzo(b,f)thiepin-ll-yl)-1-piperazinyl)- propionamidu, který představuje dlouhodobě a vysoce účinné neuroleptikum pro perorálni podávání. Látka je použitelná v therapii schizofrenních psychos. Předmětem řešení je způsob přípravy látky vzorce I, který spočívá v substituční reakci 11-chlor- -7-fluor~2-isopropyl-10,11-dihydrodibenzo- (b,f)thiepinu s 3-(1-piperazinyl)propionamidem, provedené nejlépe za použití 100% přebytku 3-(1-piperaziThe solution is within the synthetic field drugs. His subject is a method of preparation new fluorinated 10-piperazino-10,11- -dihydrodibenzo (b, f) thiepine of formula I (I) j j. 3- (4- (7-Fluoro-2-isopropyl-10,11-dihydrodibenzo (b, f) thiepin-11-yl) -1-piperazinyl) - propionamide, which is long-term and a highly effective neuroleptic for oral administration administration. The substance is useful in therapy schizophrenic psychos. The subject of the solution is a process for the preparation of a compound of formula (I) which is the substitution reaction of 11-chloro- -7-fluoro-2-isopropyl-10,11-dihydrodibenzo- (b, f) thiepine with 3- (1-piperazinyl) propionamide, best done using 100% excess 3- (1-piperazine)
Description
Vynález se týká způsobu přípravy nového fluorovaného 10-piperazino-10,11-dihydrodibenzo(b,f)thiepinu vzorce IThe present invention relates to a process for the preparation of a novel fluorinated 10-piperazino-10,11-dihydrodibenzo (b, f) thiepine of the formula I
(I) tj. 3-(4-(7-fluor-2-isopropyl-10,11-dihydrodibenzo(b,f)thiepín-ll-yl)-1-piperazinyl)propíonamidu.(I) ie 3- (4- (7-fluoro-2-isopropyl-10,11-dihydrodibenzo (b, f) thiepin-11-yl) -1-piperazinyl) propionamide.
Látka vzorce I podle vynálezu je vysoce účinným neuroleptikem, jehož účinek je silně protrahován. Umožňuje to podávání nízkých dávek v dlouhých časových intervalech, oož znamená menší zatěžování pacientů a možnost snazší kontroly užívání preparátu. Látka se používá k léčbě schizofrenních psychos. Lze ji podávat orálně ve formě base nebo ve formě solí.The compound of the formula I according to the invention is a highly potent neuroleptic whose action is strongly protracted. This allows low doses to be administered at long intervals, which means less burden on patients and makes it easier to control the use of the product. The substance is used to treat schizophrenic psychoses. It can be administered orally in base or salt form.
Způsob přípravy látky vzorce I podle tohoto vynálezu spočívá v substituční reakci známého ll-chlor-7-fluor-2-isopropyl-10,11-dihydrodibenzo(b,f)thiepinu (Jílek J. et al.: Collect. Czech. Chem. Commun. 49, 2 638, 1984) s rovněž známým 3-(1-piperazinyl)propionamidem (US patent 3 352 866) . Tuto substituční reakci lze provést za různých podmínek. Reakce probíhá velmi dobře za použiti 100% přebytku 3-(1-piperazinyl)propionamidu a ve vroucím chloroformu jako reakčním prostředí. Lze použít též jiných rozpouštědel jako prostředí, např. acetonu, acetonitrilu, benzenu, dimetylformamidu, hexametyltriamidu kyseliny fosforečné atd. Lze pracovat též bez prostředí a zahřívat obě komponenty na teploty 100 až 120 °C. Při použití ekvivalentu 3-(1-piperazinyl)propionamidu je nutné pracovat za přítomnosti látek, které váží chlorovodík, reakcí vznikající, např. bezvodého uhličitanu draselného nebo terciárních aminů, např. pyridinu nebo trietylaminu.The process for the preparation of the compound of formula I according to the invention consists in the substitution reaction of the known 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo (b, f) thiepine (Jílek J. et al .: Collect. Czech. Chem. Commun., 49, 2638, 1984) with the known 3- (1-piperazinyl) propionamide (U.S. Pat. No. 3,352,866). This substitution reaction can be carried out under various conditions. The reaction proceeds very well using a 100% excess of 3- (1-piperazinyl) propionamide and in boiling chloroform as the reaction medium. Other solvents can also be used as media, such as acetone, acetonitrile, benzene, dimethylformamide, hexamethylphosphoric triamide, etc. It is also possible to work without the environment and heat both components to temperatures of 100 to 120 ° C. When using the equivalent of 3- (1-piperazinyl) propionamide, it is necessary to work in the presence of hydrogen chloride-binding substances by reactions resulting, for example, anhydrous potassium carbonate or tertiary amines, such as pyridine or triethylamine.
Za některých těchto podmínek však vzniká ve větší míře, než za podmínek popsaných v dále uvedeném příkladu, nežádoucí produkt eliminační reakce, kterým je 2-isopropyl-7-fluordibenzo(b,f)thiepin.However, under some of these conditions, the undesired elimination reaction product, 2-isopropyl-7-fluorodibenzo (b, f) thiepine, is formed to a greater extent than under the conditions described in the example below.
Jak již bylo uvedeno, je látka vzroce I podle vynálezu nová. Její identita byla zajištěna nejen analyticky, ale také pomocí spekter. Produkt je krystalická base vzorce I, která krystaluje z vody jako hemihydrát. Solvát si zachovává své složení i při rekrystalisaci ze směsi etanolu a petroletheru; jeho t.t. je 108 až 111 °C. Dále uvedený příklad popisuje preferovanou variantu provedení přípravy látky vzorce I ve smyslu vynálezu. Je to tedy pouhá ilustrace provedení vynálezu, ale není jeho úkolem popisovat vyčerpávajícím způsobem všechny možnosti vynálezu.As already mentioned, the substance of formula I according to the invention is novel. Its identity was ensured not only analytically, but also by means of spectra. The product is a crystalline base of formula I which crystallizes from water as a hemihydrate. The solvate retains its composition even when recrystallized from a mixture of ethanol and petroleum ether; its m.p. mp 108-111 ° C. The following example describes a preferred embodiment of the preparation of a compound of formula I within the meaning of the invention. It is therefore merely an illustration of an embodiment of the invention, but is not intended to fully describe all the possibilities of the invention.
Roztok 9,2 g ll-chlor-7-fluor-2-isopropyl-10,11-dihydrodibenzo(b,f)thiepinu a 9,5 g 3-(1-piperazinyl)propionamidu v 25 ml chloroformu se míchá a vaří 15 h pod zpětným chladičem. Po ochlazení se směs zfiltruje a filtrát se odpaří za sníženého tlaku. Zbytek se zředí 100 ml vlažné (40 °C) vody a směs se extrahuje teplým benzenem. Z benzenové fáze se produkt extrahuje dvakrát do 50 ml 10% roztoku kyseliny methansulfonové. Spojené kyselé extrakty se zalkalisuji 30 ml vodného amoniaku, uvolněná krystalická base se po stání přes noc zfiltruje, promyje vodou a vysuší ve vakuu. Ve výtěžku 8,0 g (61 %) se získá hemihydrát žádané látky vzorce I, který po krystalisaci ze směsi etanolu a petroletheru taje při 108 až 111 °C.A solution of 9.2 g of 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo (b, f) thiepine and 9.5 g of 3- (1-piperazinyl) propionamide in 25 ml of chloroform is stirred and boiled. h under reflux. After cooling, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was diluted with 100 mL of lukewarm (40 ° C) water and extracted with warm benzene. The product from the benzene phase is extracted twice into 50 ml of a 10% methanesulfonic acid solution. The combined acidic extracts were made alkaline with 30 ml of aqueous ammonia, the liberated crystalline base was filtered overnight, washed with water and dried in vacuo. Yield 8.0 g (61%) of the desired compound of formula (I), which, upon crystallization from ethanol / petroleum ether, melts at 108-111 ° C.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS868290A CS256228B1 (en) | 1986-11-14 | 1986-11-14 | Method of new fluorinated 10-piperazino-10,11-dihydrodibenzo(b,f)-thiepine preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS868290A CS256228B1 (en) | 1986-11-14 | 1986-11-14 | Method of new fluorinated 10-piperazino-10,11-dihydrodibenzo(b,f)-thiepine preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS829086A1 CS829086A1 (en) | 1987-08-13 |
| CS256228B1 true CS256228B1 (en) | 1988-04-15 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS868290A CS256228B1 (en) | 1986-11-14 | 1986-11-14 | Method of new fluorinated 10-piperazino-10,11-dihydrodibenzo(b,f)-thiepine preparation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS256228B1 (en) |
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1986
- 1986-11-14 CS CS868290A patent/CS256228B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS829086A1 (en) | 1987-08-13 |
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