CS202457B1 - Method of preparing non-cataleptic neurolepticum 2-chlor-10/4-/2-hydroxyethyl/piperazino/-10,11-dihydrodibenzo/b,f/thiepine - Google Patents
Method of preparing non-cataleptic neurolepticum 2-chlor-10/4-/2-hydroxyethyl/piperazino/-10,11-dihydrodibenzo/b,f/thiepine Download PDFInfo
- Publication number
- CS202457B1 CS202457B1 CS131879A CS131879A CS202457B1 CS 202457 B1 CS202457 B1 CS 202457B1 CS 131879 A CS131879 A CS 131879A CS 131879 A CS131879 A CS 131879A CS 202457 B1 CS202457 B1 CS 202457B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- hydroxyethyl
- thiepine
- dihydrodibenzo
- piperazino
- chloro
- Prior art date
Links
- 230000002903 catalepsic effect Effects 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims description 5
- 239000003176 neuroleptic agent Substances 0.000 title claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 title claims description 4
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 title 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 230000000701 neuroleptic effect Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 239000000155 melt Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 238000001953 recrystallisation Methods 0.000 claims 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 claims 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 239000000908 ammonium hydroxide Substances 0.000 claims 1
- 239000008346 aqueous phase Substances 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 239000003610 charcoal Substances 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 239000000706 filtrate Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(54) Způsob přípravy nekataleptického neuroleptika 2-chlor-10-/4-(2-hydroxyethyl) piperazino/-10,ll-dihydrodibenzo (b,f) thiepinu(54) A process for the preparation of the non-cataleptic neuroleptic 2-chloro-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine
Tento vynález se týká nového způsobu přípravy nekataleptického neuroleptika 2-chlor -10-/4-(2-h|ydro|xyethyl)piperazino/-10,ll-dihydrodibenzo(b,f)thiepinu vzorce I.This invention relates to a novel process for the preparation of the non-cataleptic neuroleptic 2-chloro-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine of formula I.
Nyní bylo zjištěno, že jako- východiska synthesy látky vzorce I lze použít synthetického prekursoru 2,10-dichlor-10,11-dihydrodibenzo(b,f)thiepinu, kterým je 2-chlor-10, ll-dihydriOdibenzo(b,f)thiepin-10-ol (K. Pelz a spol., Collect. Czech. Chem. Commun. 33, 1852, 1968) vzorce IIIt has now been found that the synthetic precursor of 2,10-dichloro-10,11-dihydrodibenzo (b, f) thiepine, which is 2-chloro-10,11-dihydroxodibenzo (b, f), can be used as a starting point for the synthesis of the compound of formula I thiepin-10-ol (K. Pelz et al., Collect. Czech. Chem. Commun. 33, 1852, 1968) of formula II
Látka vzorce I a její soli, zejména sukcinát, vykazují vlastnosti neuroleptika téměř prostého kataleptického účinku (A. Dlahač a spol., Activ. Nerv. Super. 17, 217, 1973; Z. Votava a spol., tamtéž, str. 216; M. Valchář a A. Dlabač, Cesk. Fysiol. 23, 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 which is almost free of cataleptic activity (A. Dlahac et al., Activ. Nerv. Super. 17, 217, 1973; Z. Votava et al., Ibid., P. 216; M. Valchar and A. Dlabac, Cesk Fysiol., 23, 277, 1976; LG Humber et al., J. Med. Chem. 21, 1225, 1978), suggesting that it is a potentially limited antipsychotic drug. extrapyramidal side effects.
Příprava látky vzorce I byla popsána substituční reakcí 2,10-dichlor-10,ll-dihydrodibenzo(b,f) thiepinu s l-(2-hydroxyethyl)piperazinem (J. O. Jílek a spol., Collect. Czech. Chem. Commun. 40, 2887, 1973). Nevýhodou této metody je, že je ve značné míře (okolo 35 °/o) provázena vedlejší eliminační reakcí, jejímž produktem je nežádoucí 2-chlordiběnzo(b,f)thiepin.The preparation of the compound of formula I has been described by the substitution reaction of 2,10-dichloro-10,11-dihydrodibenzo (b, f) thiepine with 1- (2-hydroxyethyl) piperazine (JO Jílek et al., Collect. Czech. Chem. Commun. 40 2887, 1973). The disadvantage of this method is that it is to a large extent (about 35%) accompanied by a side elimination reaction, the product of which is the undesirable 2-chlorodibenzo (b, f) thiepine.
Tento alkohol reaguje v pyridinu s chloridy alkansulfonových nebo arensulfonových kyselin s 1 až 7 atomy uhlíku za vzniku sulfoesterů, které lze bez isolace přímo „in šitu“ zpracovat působením l-(2-hydroxyethyl) piperazinu, přičemž resultuje žádaná báze vzorce I. Tento nový způsob přípravy látky vzorce I je předmětem tohoto vynálezu. Reakce alkoholu vzorce II s alkan- nebo arensulfonylchloridy v pyridinu se provádí za chladu, s výhodou při 0 až 5 °C. Následující reakce s l-(2-hydroxyethyl)piperazinem probíhá při teplotě místnosti. Jako sulfonylchloridů lze s výhodou použít methan-sulfonylchloridu, benzensulfonylchloridu, p-toluensulfonylchloridu, o-toluensulfonylchloridu, p-hrombenzensulfonylchloridu apod. Isolace produktu vzorce I využívá výbornéThis alcohol reacts in pyridine with C 1 -C 7 alkanesulfonic or arensulfonic acid chlorides to form sulfoesters which can be treated directly in situ without isolation with 1- (2-hydroxyethyl) piperazine to give the desired base of Formula I. This new a process for preparing a compound of formula I is an object of the present invention. The reaction of the alcohol of formula II with alkane or arenesulfonyl chlorides in pyridine is carried out in the cold, preferably at 0 to 5 ° C. The following reaction with 1- (2-hydroxyethyl) piperazine is carried out at room temperature. As sulfonyl chlorides, it is advantageous to use methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, o-toluenesulfonyl chloride, p-thiobenzenesulfonyl chloride and the like.
20W7 rozpustnosti pyridinu a l-( 2-hydroxyethyl] piperazinu ve vodě. Jako nerozpustná komponenta směsi a současně jako látka bazická se isoluje žádaná látka vzorce I. Ta je jako báze krystalická, krystaluje výborně z acetonu a v čistém stavu taje při 102 až 103 °C. Neutralisací kyselinou jantarovou poskytuje krystalický sukcinát, který krystaluje z ethanolu a v čistém stavu taje při 166 až 168 °C. Příklad provedení20W7 solubility of pyridine and 1- (2-hydroxyethyl) piperazine in water As the insoluble component of the mixture and at the same time as the basic substance, the desired compound of formula I is isolated. This is crystalline as a base, crystallizes excellently from acetone. Neutralization with succinic acid gives a crystalline succinate which crystallizes from ethanol and melts in the pure state at 166-168 ° C.
K míchání roztoku 26 g 2-chlor-10,ll-dihydrodibenzo(b,f )thiepin-10-olu (K. Pelz a spol., literatura citována) v 80 ml pyridinu se při 0—5 °C zvolna přikape 11,4 g methansulfonylchloridu. Směs se míchá 1 hodinu při teplotě místnosti, potom se přidá 52 g 1-(2-hydroxyethyl)piperazinu, míchá se další 1 hodinu při teplotě místnosti a potom se ponechá 48 hodin v klidu. Zředí se potomTo stir a solution of 26 g of 2-chloro-10,11-dihydrodibenzo (b, f) thiepine-10-ol (K. Pelz et al., Literature cited) in 80 ml of pyridine at 0-5 ° C is slowly added dropwise 11, 4 g of methanesulfonyl chloride. The mixture is stirred for 1 hour at room temperature, then 52 g of 1- (2-hydroxyethyl) piperazine are added, stirred for a further 1 hour at room temperature and then left to stand for 48 hours. It is then diluted
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS131879A CS202457B1 (en) | 1979-02-27 | 1979-02-27 | Method of preparing non-cataleptic neurolepticum 2-chlor-10/4-/2-hydroxyethyl/piperazino/-10,11-dihydrodibenzo/b,f/thiepine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS131879A CS202457B1 (en) | 1979-02-27 | 1979-02-27 | Method of preparing non-cataleptic neurolepticum 2-chlor-10/4-/2-hydroxyethyl/piperazino/-10,11-dihydrodibenzo/b,f/thiepine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS202457B1 true CS202457B1 (en) | 1981-01-30 |
Family
ID=5347258
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS131879A CS202457B1 (en) | 1979-02-27 | 1979-02-27 | Method of preparing non-cataleptic neurolepticum 2-chlor-10/4-/2-hydroxyethyl/piperazino/-10,11-dihydrodibenzo/b,f/thiepine |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS202457B1 (en) |
-
1979
- 1979-02-27 CS CS131879A patent/CS202457B1/en unknown
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