CH385848A - Process for the preparation of basic phenothiazine derivatives which are substituted in the 3-position by a monovalent sulfur function - Google Patents
Process for the preparation of basic phenothiazine derivatives which are substituted in the 3-position by a monovalent sulfur functionInfo
- Publication number
- CH385848A CH385848A CH1543463A CH1543463A CH385848A CH 385848 A CH385848 A CH 385848A CH 1543463 A CH1543463 A CH 1543463A CH 1543463 A CH1543463 A CH 1543463A CH 385848 A CH385848 A CH 385848A
- Authority
- CH
- Switzerland
- Prior art keywords
- substituted
- basic
- phenothiazine derivatives
- preparation
- phenothiazine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- 229940066767 systemic antihistamines phenothiazine derivative Drugs 0.000 title claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title claims description 4
- 125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229950000688 phenothiazine Drugs 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 150000002990 phenothiazines Chemical class 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- -1 aralkyl halides Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- YIUIVFFUEVPRIU-UHFFFAOYSA-N 8-chlorotheophylline Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21 YIUIVFFUEVPRIU-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229940072033 potash Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000002908 adrenolytic effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000009835 boiling Methods 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
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 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
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 201000003152 motion sickness Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Verfahren zur Herstellung von basischen Phenothiazin-Derivaten, die in 3-Stellung mit einer einwertigen Schwefelfunktion substituiert sind Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von basischen Phenothiazin-Deriva- ten, die in 3-Stellung mit einer einwertigen Schwefel funktion substituiert sind, und die der allgemeinen Formel I
EMI0001.0005
entsprechen, wobei R1 eine Alkyl- mit mindestens 2 Kohlenstoffatomen, Aryl- oder Aralkylgruppe, R2 ein Wasserstoffatom oder eine Methylgruppe und R3 eine gerade oder verzweigte Alkylgruppe mit 1 bis 4 Kohlenstoffatomen oder eine Aralkylgruppe bedeu ten.
Solche Verbindungen werden erfindungsgemäss hergestellt, indem Phenothiazin-Derivate der Formel II,
EMI0001.0006
alkyliert oder aralkyfiert werden. Die Ausführung des erfindungsgemässen Ver fahrens erfolgt beispielsweise so, dass eine Verbin dung der allgemeinen: Formel II mit Alkyl- bzw. Aralkyl-halogeniden in Anwesenheit eines Lösungs mittels, wie z. B. eines niederen Alkohols, Benzol, Toluol, Xylol und dergleichen umgesetzt wird, wo bei ein alkalisches Kondensationsmittel, wie z. B. Natrium- oder Kaliumbicarbonat, Natrium- oder Kaliumcarbonat, verwendet werden kann.
Die Ver bindungen der - allgemeinen Formel II können bei spielsweise so hergestellt werden, dass- man eine Lö sung einer Verbindung der allgemeinen Formel III
EMI0001.0010
in einem geeigneten organischen Lösungsmittel, wie z. B. einem niederen aliphatischen Alkohol, Benzol, Tolual, Xylol, Dichlorbenzol, Nitrobenzol und der gleichen, mit Piperazin kondensiert, wobei man ent weder das Piperazin im Überschuss anwendet oder ein anderes alkalisches Kondensationsmittel, wie z. B. Natrium- oder Kaliumhydroxyd oder Natrium- oder Kaliumcarbonat, verwendet.
Für den Fall, dass R3 für eine Methylgruppe steht, kann die Alkyliexung auch reduktiv mit Ameisensäure und Formaldehyd durchgeführt werden. Nach beendeter Umsetzung kann das Reaktions gemisch von anorganischem Material abfiltriert oder mit Wasser ausgeschüttelt und das Lösungsmittel unter vermindertem Druck abgedampft werden; die neuen Substanzen können aber auch aus dem Reak tionsgemisch durch verdünnte Mineral- oder orga nische Säuren extrahiert und aus der wässerigen Phase durch Versetzen mit Laugen bzw. Ammoniak ausgeschieden werden.
Die Basen können abfiltriert werden, wenn sie sich in festem Zustand abscheiden oder, wenn sie ölig ausfallen, in Benzol oder einem andern mit Wasser nicht mischbaren Lösungsmittel aufgenommen und dann vom Lösungsmittel durch Eindampfen wieder befreit werden. Die Basen kön nen durch Destillation im Hochvakuum gereinigt und in ein geeignetes Salz mit organischen oder anorga nischen Säuren sowie z. B. mit 8-Chlor-theophyllin übergeführt werden.
Die nach dem vorliegenden Verfahren hergestell ten, bisher unbekannten basischen Phenothiazin- Derivate sind bei Zimmertemperatur ölig oder kri- stallin und bilden mit anorganischen und organischen Säuren sowie z. B. mit 8-Chlor-theophyllin bei Zimmertemperatur kristalline, beständige Salze.
Die verfahrensgemäss hergestellten, in dem nach folgenden Beispiel beschriebenen Verbindungen be sitzen wertvolle pharmakodynamische Eigenschaften und sollen deshalb in der Therapie zur Bekämpfung von Erregungs- und Spannungszuständen bei psychi schen Erkrankungen verwendet werden. Es hat sich gezeigt, dass bei Phenothiazin-Derivaten, die in 3-Stellung des Phenothiazingerüstes eine Äthyl- mercaptogruppe tragen, die adrenolytische Wirkung am stärksten ausgeprägt ist. Phenothiazine, die in 10- Stellung durch einen Piperazinylpropyl-Rest substi tuiert sind, haben über die sedative Wirkung hinaus noch eine starke antiemetische Wirkung und können dementsprechend verwendet werden, wie z.
B. bei Reisekrankheit oder bei Schwangerschaftserbrechen. Die nach dem vorliegenden Verfahren hergestellten Substanzen können entweder per os in Dragees oder auch parenteral, z. B. subcutan, verabreicht werden. In dem nachfolgenden Beispiel erfolgen alle Tempe raturangaben in Celsiusgraden. Die Schmelzpunkte sind unkorrigiert. <I>Beispiel</I> 3-Athylmercapto-10-[3'-(1"-methyl piperazyl-4")- propyl-1'] phenothiazin Ein Gemisch von 90,0 g 3 Äthylmercapto-10- (3'-chlorpropyl-1')-phenothiazin, 46,1g wasserfreiem Piperazin und 100 cm3 n-Butanol wird unter Rühren während 20 Stunden bei 120 Ölbadtemperatur er hitzt.
Nach dem Abkühlen wird mit 300 cm3 Toluol verdünnt und mit dreimal je 100 cm3 Wasser aus geschüttelt. Dann wird mit 720 cm3 15 % iger wässeriger Weinsäure extrahiert. Der Weinsäure extrakt wird mit zweimal je 50 cm3 Toluol ausge waschen, mit 180 cm3 konz. Natronlauge phenol- phthalein-alkalisch gestellt und die ausgeschiedene ölige Base in total 500 cm3 Benzol aufgenommen. Nach dem Waschen der Benzolschicht mit zweimal je 100 cm3 Wasser wird über Pottasche getrocknet, filtriert und unter vermindertem Druck eingedampft. Der Eindampfrückstand wird im Hochvakuum destil liert; nach Abtrennen eines unter 0,02 mm bis 229 übergehenden Vorlaufs fängt man die unter dem gleichen Druck bei 229-233 destillierende Haupt fraktion auf.
Die analysenreine Base, das 3 Äthyl- mercapto -10 - [3' - (piperazyl -1")-propyl-1'-pheno- thiazin hat den Siedepunkt 231 j0,02 mm Hg.
Zur Herstellung des Dimaleinates wird eine Lö sung von 13,2 g der freien Base in 100 cm3 abs. Äthanol zu einer heissen Lösung von 8,3g Malein säure in 75 cm3 abs. Äthanol zugegeben. Nach dem Umkristallisieren des ausgeschiedenen Salzes aus abs. Äthanol erhält man das analysenreine Dimaleinat des 3 Äthylmercapto-10-[3'-(piperazyl-1")-propyl-1']- phenothiazins vom Zersetzungspunkt 154-156 nach Sintern ab 143 .
3-Äthylmercapto-10-[3'-(1"-methyl-piperazyl-4")- propyl- 1']-phenothiazin 5,9 g 3 -Äthylmercapto-10 - [3'-(piperazyl-1")- propyl-1']-phenothiazin, 1,9 cm3 90% aige Ameisen säure und 2,0 cm3 wässeriges 30o/o-iges Formaldehyd werden zusammen während 9 Stunden im Ölbad von 120 erhitzt. Dann wird das Reaktionsgemisch in 25 cm3 Wasser aufgenommen, mit 20 cm3 3n Na tronlauge bis zur phenolphthalein-alkalischen Reak tion versetzt und die ausgeschiedene Base in total 50 cm3 Benzol aufgenommen. Nach dem Waschen mit 20 cm3 Wasser wird über Pottasche getrocknet, filtriert und eingeengt.
Der Eindampfrückstand wird im Hochvakuum destilliert. Nach Abtrennen eines unter 0,01 mm Hg bis 226 übergehenden Vorlaufes fängt man die unter dem gleichen Druck bei 226 bis 228 destillierende Hauptfraktion auf. Nach dem Kristallisieren aus Aceton erhält man das analysen reine 3 -Äthylmercapto-10-[3'-(1"-methyl-piperazyl- 4")-propyl-1']-phenothiazin vom konstanten Smp. 62-64 .
Process for the preparation of basic phenothiazine derivatives which are substituted in the 3-position with a monovalent sulfur function. The present invention relates to a process for the preparation of basic phenothiazine derivatives which are substituted in the 3-position with a monovalent sulfur function those of the general formula I.
EMI0001.0005
where R1 is an alkyl group with at least 2 carbon atoms, an aryl or aralkyl group, R2 is a hydrogen atom or a methyl group and R3 is a straight or branched alkyl group with 1 to 4 carbon atoms or an aralkyl group.
Such compounds are prepared according to the invention by using phenothiazine derivatives of the formula II,
EMI0001.0006
alkylated or aralkyfed. The inventive method is carried out, for example, so that a connec tion of the general: Formula II with alkyl or aralkyl halides in the presence of a solvent means such. B. a lower alcohol, benzene, toluene, xylene and the like is reacted, where an alkaline condensing agent, such as. B. sodium or potassium bicarbonate, sodium or potassium carbonate, can be used.
The compounds of the general formula II can, for example, be prepared in such a way that a solution of a compound of the general formula III
EMI0001.0010
in a suitable organic solvent, such as. B. a lower aliphatic alcohol, benzene, toluene, xylene, dichlorobenzene, nitrobenzene and the like, condensed with piperazine, whereby ent neither the piperazine applied in excess or another alkaline condensing agent, such as. B. sodium or potassium hydroxide or sodium or potassium carbonate is used.
In the event that R3 stands for a methyl group, the alkylation can also be carried out reductively with formic acid and formaldehyde. After the reaction has ended, the inorganic material can be filtered off the reaction mixture or extracted with water and the solvent evaporated under reduced pressure; However, the new substances can also be extracted from the reaction mixture using dilute mineral or organic acids and eliminated from the aqueous phase by adding alkalis or ammonia.
The bases can be filtered off if they separate out in the solid state or, if they precipitate out oily, taken up in benzene or another water-immiscible solvent and then freed from the solvent again by evaporation. The bases can NEN purified by distillation in a high vacuum and converted into a suitable salt with organic or inorganic acids and z. B. be transferred with 8-chloro-theophylline.
The previously unknown basic phenothiazine derivatives produced by the present process are oily or crystalline at room temperature and form with inorganic and organic acids and z. B. with 8-chloro-theophylline crystalline, stable salts at room temperature.
The compounds prepared according to the process and described in the following example have valuable pharmacodynamic properties and should therefore be used in therapy to combat states of excitement and tension in mental illnesses. It has been shown that the adrenolytic effect is most pronounced in the case of phenothiazine derivatives which have an ethyl mercapto group in the 3-position of the phenothiazine structure. Phenothiazines, which are substituted in the 10-position by a piperazinylpropyl radical, have a strong antiemetic effect in addition to the sedative effect and can therefore be used, such as.
B. in the case of motion sickness or vomiting. The substances prepared by the present process can either per os in coated tablets or parenterally, e.g. B. subcutaneously administered. In the following example, all temperatures are given in degrees Celsius. The melting points are uncorrected. <I> Example </I> 3-Ethylmercapto-10- [3 '- (1 "-methyl piperazyl-4") -propyl-1'] phenothiazine A mixture of 90.0 g of 3 ethylmercapto-10- (3 ' -chlorpropyl-1 ') - phenothiazine, 46.1g of anhydrous piperazine and 100 cm3 of n-butanol is heated with stirring for 20 hours at 120 oil bath temperature.
After cooling, it is diluted with 300 cm3 of toluene and shaken out three times with 100 cm3 of water each time. Then it is extracted with 720 cm3 of 15% aqueous tartaric acid. The tartaric acid extract is washed out twice with 50 cm3 of toluene each time, with 180 cm3 of conc. Sodium hydroxide solution made phenol-phthalein-alkaline and the oily base which separated out was taken up in a total of 500 cm3 of benzene. After washing the benzene layer with twice 100 cm3 of water, it is dried over potash, filtered and evaporated under reduced pressure. The evaporation residue is distilled in a high vacuum; after separating a forerun that passes under 0.02 mm to 229, the main fraction distilling under the same pressure at 229-233 is collected.
The analytically pure base, the 3 ethyl mercapto -10 - [3 '- (piperazyl -1 ") - propyl-1'-phenothiazine, has a boiling point of 231 ± 0.02 mm Hg.
A solution of 13.2 g of the free base in 100 cm3 of abs Ethanol to a hot solution of 8.3g maleic acid in 75 cm3 abs. Ethanol added. After recrystallization of the precipitated salt from abs. Ethanol, the analytically pure dimaleate of 3 ethyl mercapto-10- [3 '- (piperazyl-1 ") - propyl-1'] - phenothiazine is obtained from the decomposition point 154-156 after sintering from 143.
3-ethylmercapto-10- [3 '- (1 "-methyl-piperazyl-4") - propyl- 1'] - phenothiazine 5.9 g 3 -ethylmercapto-10 - [3 '- (piperazyl-1 ") - propyl-1 '] phenothiazine, 1.9 cm3 of 90% formic acid and 2.0 cm3 of aqueous 30% formaldehyde are heated together for 9 hours in an oil bath of 120. The reaction mixture is then taken up in 25 cm3 of water, 20 cm3 of 3N sodium hydroxide solution are added to the phenolphthalein-alkaline reaction, and the base which has precipitated is taken up in a total of 50 cm3 of benzene.After washing with 20 cm3 of water, it is dried over potash, filtered and concentrated.
The evaporation residue is distilled in a high vacuum. After separating off a forerun which is below 0.01 mm Hg up to 226, the main fraction distilling under the same pressure at 226 to 228 is collected. After crystallization from acetone, the analytically pure 3-ethylmercapto-10- [3 '- (1 "-methyl-piperazyl-4") - propyl-1'] - phenothiazine of constant melting point 62-64 is obtained.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1543463A CH385848A (en) | 1959-08-12 | 1959-08-12 | Process for the preparation of basic phenothiazine derivatives which are substituted in the 3-position by a monovalent sulfur function |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH7686859A CH376505A (en) | 1959-08-12 | 1959-08-12 | Process for the preparation of basic phenothiazine derivatives which are substituted in the 3-position by a monovalent sulfur function |
| CH1543463A CH385848A (en) | 1959-08-12 | 1959-08-12 | Process for the preparation of basic phenothiazine derivatives which are substituted in the 3-position by a monovalent sulfur function |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH385848A true CH385848A (en) | 1964-12-31 |
Family
ID=25716411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1543463A CH385848A (en) | 1959-08-12 | 1959-08-12 | Process for the preparation of basic phenothiazine derivatives which are substituted in the 3-position by a monovalent sulfur function |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH385848A (en) |
-
1959
- 1959-08-12 CH CH1543463A patent/CH385848A/en unknown
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