CH404669A - Process for the preparation of alkyl mercapto-phenothiazine derivatives - Google Patents
Process for the preparation of alkyl mercapto-phenothiazine derivativesInfo
- Publication number
- CH404669A CH404669A CH175362A CH175362A CH404669A CH 404669 A CH404669 A CH 404669A CH 175362 A CH175362 A CH 175362A CH 175362 A CH175362 A CH 175362A CH 404669 A CH404669 A CH 404669A
- Authority
- CH
- Switzerland
- Prior art keywords
- methyl
- preparation
- dithiohydroquinone
- chlorophenyl
- phenothiazine derivatives
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 3
- -1 alkyl mercapto-phenothiazine derivatives Chemical class 0.000 title description 12
- 150000002990 phenothiazines Chemical class 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 3
- WYLQRHZSKIDFEP-UHFFFAOYSA-N benzene-1,4-dithiol Chemical class SC1=CC=C(S)C=C1 WYLQRHZSKIDFEP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229940066767 systemic antihistamines phenothiazine derivative Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- JZROAVSLDUAQEI-UHFFFAOYSA-N 3-methylsulfanyl-10H-phenothiazine Chemical compound C1=CC=C2SC3=CC(SC)=CC=C3NC2=C1 JZROAVSLDUAQEI-UHFFFAOYSA-N 0.000 description 2
- YOAFILPTKZIYAB-UHFFFAOYSA-N CC=1C=C(C=2NC3=CC=CC=C3SC2C1)S Chemical compound CC=1C=C(C=2NC3=CC=CC=C3SC2C1)S YOAFILPTKZIYAB-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940072033 potash Drugs 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- FRCDSGBFLHMDBG-UHFFFAOYSA-N 1-(2-chloro-5-oxophenothiazin-10-yl)-3-(dimethylamino)propan-1-one Chemical class C1=C(Cl)C=C2N(C(=O)CCN(C)C)C3=CC=CC=C3S(=O)C2=C1 FRCDSGBFLHMDBG-UHFFFAOYSA-N 0.000 description 1
- AQEGPOZOEITDSL-UHFFFAOYSA-N 1-bromo-4-methylsulfanyl-2-nitrobenzene Chemical compound CSC1=CC=C(Br)C([N+]([O-])=O)=C1 AQEGPOZOEITDSL-UHFFFAOYSA-N 0.000 description 1
- UFLRXTNPCRROEB-UHFFFAOYSA-N 1-chloro-4-methylsulfanyl-2-nitrobenzene Chemical compound CSC1=CC=C(Cl)C([N+]([O-])=O)=C1 UFLRXTNPCRROEB-UHFFFAOYSA-N 0.000 description 1
- IDAYFOARKWEBPH-UHFFFAOYSA-N 2-(2-bromophenyl)sulfanyl-5-methylsulfanylaniline Chemical compound NC1=CC(SC)=CC=C1SC1=CC=CC=C1Br IDAYFOARKWEBPH-UHFFFAOYSA-N 0.000 description 1
- YUQUNWNSQDULTI-UHFFFAOYSA-N 2-bromobenzenethiol Chemical compound SC1=CC=CC=C1Br YUQUNWNSQDULTI-UHFFFAOYSA-N 0.000 description 1
- PWOBDMNCYMQTCE-UHFFFAOYSA-N 2-chlorobenzenethiol Chemical compound SC1=CC=CC=C1Cl PWOBDMNCYMQTCE-UHFFFAOYSA-N 0.000 description 1
- BUORSADLRYESMM-UHFFFAOYSA-N 2-methyl-10H-phenothiazine-1-thiol Chemical compound CC1=C(C=2NC3=CC=CC=C3SC=2C=C1)S BUORSADLRYESMM-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical group C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- VLEYFOVOXARRNF-UHFFFAOYSA-N n-[2-(2-bromophenyl)sulfanyl-5-methylsulfanylphenyl]acetamide Chemical compound CC(=O)NC1=CC(SC)=CC=C1SC1=CC=CC=C1Br VLEYFOVOXARRNF-UHFFFAOYSA-N 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical group C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000004073 vulcanization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
- C08K5/0025—Crosslinking or vulcanising agents; including accelerators
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
Verfahren zur Herstellung von Alkylmercapto-Phenothiazin-Derivaten Es wurde gefunden, dass man zu in 3-Stellung durch eine einwertige Schwefelfunktion substituier ten Phenothiazinen der allgemeinen Formel I, worin R eine niedere Alkylgruppe bedeutet, gelangen kann, indem man ein Dithiohydrochinon-Derivat der all gemeinen Formel II, worin jeweils ein X Chlor,
Brom oder Jod und das andere X eine gegebenenfalls durch einen niederen aliphatischen oder einen aro matischen Acylrest substituierte Aminogruppe be deutet, einem Ringschluss unterwirft.
Die Ausführung des Verfahrens erfolgt beispiels weise so, dass man ein Dithiohydrochinon-Derivat der allgemeinen Formel II in einem höher siedenden Lösungsmittel, wie z. B. Xylol, Chlorbenzol, Tetralin oder Dimethylformamid, in Anwesenheit eines .alkali schen Kondensationsmittel, wie z. B.
Natrium= oder Kaliumcarbonat, und etwas Kupferpulver erhitzt. Wird dabei von einer Verbindung der Formel II aus gegangen, worin die Aminogruppe durch eine Acyl- gruppe substituiert ist, so hängt es von den Reak tionsbedingungen ab, ob das entstandene Acyl-Pheno- thiazin-Derivat zum Phenothiazin-Derivat entacyliert wird oder nicht. In letzterem Fall kann die Acyl- gruppe, sofern dies gewünscht wird, in einer eigenen Stufe durch alkalische Hydrolyse, z.
B. Erwärmen in einer alkoholischen Lösung von Kaliumhydroxyd, abgespalten werden. Nach beendeter Umsetzung wird von anorganischen Stoffen abfiltriert und das Filtrat durch Eindampfen vom Lösungsmittel befreit. Die Phenothiazin-Derivate werden aus dem Ein dampfrückstand durch Destillation im Hochvakuum isoliert und durch Kristallisation aus einem geeigne ten Lösungsmittel, wie z. B. Benzol, Xylol, Methanol oder Äthanol, gereinigt.
Zu den gleichen Verbindungen kann man auch gelangen, wenn man ein N-(m Alkylmercapto-phenyl)- anilin mit einem Schwefelungsmittel bei erhöhter Temperatur cyclisiert. Es ist jedoch bekannt, dass bei der Cyclisierung solcher an einem Phenylkern in m-Stellung substituierten Diphenylamin-Derivate mit Schwefelungsmittel zwei Stellungsisomere,
nämlich das 1-Alkylmercapto- und das 3-Alkylmercapto- phenothiazin-Derivat nebeneinander entstehen, die, um das gewünschte Endprodukt der Formel I zu er halten, voneinander getrennt werden müssen.
Der technische Fortschritt der vorliegenden Er findung besteht nun darin, dass keine Möglichkeit zur Bildung von 1-Alkylmercapto-phenothiazin- Derivaten besteht. Das vorliegende Verfahren ist daher besonders für die technische Herstellung der Verfahrensprodukte geeignet und gestattet es, grosse Mengen dieser Phenothiazine rationell und in guter Ausbeute herzustellen. Ein besonderer Vorteil des Verfahrens gemäss vorliegender Erfindung besteht noch darin, dass die Endprodukte in sehr reiner Form erhalten werden, was für ihre Verwendung als Zwi schenprodukt für die Synthese weiterer Derivate von grosser Wichtigkeit ist.
Die nach dem vorliegenden Verfahren herge stellten Phenothiazin-Derivate sind bei Zimmer temperatur kristallin. Sie sind brauchbare Vulkani- sationsbeschl#euniger und Antihelmintica, können aber vor allem durch geeignete Substitution am Stickstoff in hochwirksame Neuroplegica, Spasmoly- tica und narkosepotenzierende Mittel umgewandelt werden.
Im nachfolgenden Beispiel erfolgen alle Tempe raturangaben in Celsiusgraden und sind korrigiert.
EMI0002.0001
<I>Beispiel</I> 3-Methylmercaptophenothiazin a) S-Methyl-S'-(2'-chlorphenyl)-3-nitro- dithiohydrochinon. Eine Lösung von<B>150</B> g o-Chlorthiophenol, 45,7 g Natriumhydroxyd und 258 g 3-Nitro-4-brom-thio- anisol (Smp. 76-781)
in<B>1150</B> cmd abs. Äthanol wird unter Rühren während 6 Stunden am Rückfluss gekocht. Nach beendeter Reaktion wird der Alkohol unter vermindertem Druck abdestilhert, der Rück stand mit 500 cm.3 Wasser versetzt und mit 1000 cm3 Chloroform extrahiert.
Nach dem Waschen. der Chloroformlösung mit 400 cm3 1n Natronlauge und 400 cm3 Wasser wird diese über Pottasche getrock net und das Lösungsmittel verjagt.
Nach zweimaligem Umkristallisieren des Eindampfrückstandes aus Ätha- nol erhält man das analysenreine S-Methyl S'-(2'- chlorphenyl)-3-nitro-dithiohydrochinon vom Smp. 76 bis 78 .
b) S-Methyl-S'-(2'-bromphenyl)-3-nitro- dithiohydrochinon. Diese Verbindung wurde in analoger Weise zu obigem Verfahren aus o-Bromthiophenol und 3 Ni- tro - 4 -chlor - thioanisol (Smp. 73-751) hergestellt. Smp. 90-92 .
c) S-Methyl-S'-(2'-chlorphenyl)-3-amino- dithiohydrochinon. Zu einer siedenden Lösung von 200 g S-Methyl- S'-(2'-chlorphenyl) - 3-nitro-dithiohydrochinon (Smp. 76-78 ) in 5 1 Methanol wird während 11/2 Stunden unter Rühren eine Lösung von 1160g Natrium- sulfid-nonahydrat und 146g Natriumbicarbonat in 1500 cm3 Wasser zugetropft und anschliessend wei tere 12 Stunden zum Sieden erhitzt.
Nach beendeter Reaktion wird das Methanol abgedampft und der Rückstand mit 1500 cm3 Chloroform extrahiert. Die Chloroformlösung wird mit 300 cms Wasser gewa schen, über Pottasche getrocknet und das Lösungs mittel bei vermindertem Druck verjagt. Nach zwei maligem Umkristallisieren des Eindampfrückstandes aus abs. Äthanol erhält man das analysenreine S-Me- thyl - S' - (2'- chlorphenyl)-3-amino-dithiohydrochinon vom Smp. 92-94 .
d) S-Methyl-S'-(2'-bromphenyl)-3-amino- dithiohydrochinon.
Diese Verbindung wurde in analoger Weise zu obigem Verfahren aus S-Methyl-S'-(2'-bromphenyl)- 3-nitro-dithiohydrochinon (Smp. 90-92 ) hergestellt.
e) S-Methyl-S'-(2'-chlorphenyl)-3-acetamino- dithiohydrochinon.
Ein Gemisch von 845 g S-Methyl-S'-(2'-chlor- phenyl) - 3 - amino-dithiohydrochinon (Smp. 92-94 ) und 354 cm3 Essigsäureanhydrid wird während 4 Stunden in einem Ölbad von l70 am Rückfluss er hitzt.
Darauf wird das überschüssige Essigsäure anhydrid und die entstandene Essigsäure im Vakuum abgedampft und der Rückstand im Hochvakuum destilliert. Die bei einem Druck von 0,05 mm Hg von 160-170 übergehende Hauptfraktion wird auf gefangen und aus Äthanol umkristallisiert. Das ana lysenreine S-Methyl-S'-(2'-chlorphenyl)-3-acetamino- dithiohydrochinon schmilzt bei 89-91 .
f) S-Methyl-S'-(2'-bromphenyl)-3-acetamino- dithiohydrochinon.
Diese Verbindung wurde in analoger Weise zu obigem Verfahren aus S-Me@thyl-S'-(2'-bromphenyl)- 3-amno-dithiohydrochinon (Smp. 115-l17 ) herge stellt. Smp. 99-1011.
g) 3 Methylmercaptophenothiazin [durch Cyclisierung von S-Methyl-S'-(2'-brom- phenyl)-3-amino-dithiohydrochinon]. Ein Gemisch von 75,0 g S-Methyl-S'-(2'-brom- phenyl)-3-am@ino-dithiohydrochinon (Smp. 115-117 ), 7(i,0 g fein pulverisiertem Kaliumcarbonat, 2 g Kupferbronze und 450 cm3 Dimethylformamid wird während 15 Stunden unter Rühren bei 200 Ölbad temperatur am Rückfluss gekocht.
Nach dem Ab kühlen wird von anorganischen Bestandteilen abfil- triert und das Filtrat im Vakuum eingeengt. Der Eindampfrückstand wird im Hochvakuum destilliert und die bei einem Druck von 0,05 mm Hg zwischen 190 und 200 übergehende Hauptfraktion aufgefan gen und aus Äthanol umkristallisiert. Das erhaltene analysenreine 3 Methylmercaptophenothiazin hat den Smp. 138-140 .
h) 3-Methylmercaptophenothiazin [durch Cyclisierung von S-Methyl-S'-(2'-chlor- phenyl)-3-acetantno-dithiohydrochinon]. Ein Gemisch von 66,0 g S-Methyl-S'-(2'-chlor- phenyl)-3-acetamino-dithiohydrochinon (Smp. 89 bis 91'), 62,0 g fein. pulverisiertem Kaliumcarbonat,
2 g Kupferbronze und 450 cm3 Dimethylformamid wird unter Rühren während 15 Stunden bei 200 Ölbad temperatur am Rückfluss gekocht. Nach dem Ab kühlen wird von anorganischen Bestandteilen ab filtriert und das Filtrat im Vakuum eingeengt. Der Eindampfrückstand wird im Hochvakuum destilliert und die bei einem Druck von 0,05 mm Hg zwischen 190 und 200 übergehende Hauptfraktion aufgefan- gen und aus Äthanol umkristallisiert. Das erhaltene analysenreine 3-Methylmercaptophenothiazin hat den Smp. 138-140 .
Process for the preparation of alkylmercapto-phenothiazine derivatives It has been found that phenothiazines of the general formula I, in which R is a lower alkyl group, substituted in the 3-position by a monovalent sulfur function can be obtained by adding a dithiohydroquinone derivative of all common formula II, in which in each case one X is chlorine,
Bromine or iodine and the other X denotes an amino group optionally substituted by a lower aliphatic or an aromatic acyl radical, subject to a ring closure.
The method is carried out, for example, so that a dithiohydroquinone derivative of the general formula II in a higher-boiling solvent, such as. B. xylene, chlorobenzene, tetralin or dimethylformamide, in the presence of an .alkali condensing agent, such as. B.
Sodium = or potassium carbonate, and some copper powder heated. If the starting point is a compound of formula II in which the amino group is substituted by an acyl group, it depends on the reaction conditions whether the acyl-phenothiazine derivative formed is deacylated to the phenothiazine derivative or not. In the latter case, the acyl group can, if so desired, in a separate stage by alkaline hydrolysis, e.g.
B. heating in an alcoholic solution of potassium hydroxide, are split off. After the reaction has ended, inorganic substances are filtered off and the filtrate is freed from the solvent by evaporation. The phenothiazine derivatives are isolated from the A vapor residue by distillation in a high vacuum and crystallized from a suitable th solvent, such as. B. benzene, xylene, methanol or ethanol cleaned.
The same compounds can also be obtained if an N- (m-alkylmercapto-phenyl) -aniline is cyclized with a sulfurizing agent at an elevated temperature. However, it is known that in the cyclization of such diphenylamine derivatives substituted on a phenyl nucleus in the m-position with sulfurizing agent, two positional isomers,
namely the 1-alkyl mercapto and the 3-alkyl mercapto phenothiazine derivative arise side by side, which must be separated from each other in order to keep the desired end product of the formula I.
The technical progress of the present invention consists in the fact that there is no possibility of the formation of 1-alkylmercapto-phenothiazine derivatives. The present process is therefore particularly suitable for the industrial production of the process products and allows large amounts of these phenothiazines to be produced efficiently and in good yield. A particular advantage of the process according to the present invention is that the end products are obtained in a very pure form, which is of great importance for their use as an intermediate product for the synthesis of further derivatives.
The phenothiazine derivatives produced by the present process are crystalline at room temperature. They are useful vulcanization accelerators and antihelmintics, but above all by suitable substitution of nitrogen they can be converted into highly effective neuroplegics, spasmolytics and anesthetizing agents.
In the following example, all temperatures are given in degrees Celsius and have been corrected.
EMI0002.0001
<I> Example </I> 3-methyl mercaptophenothiazine a) S-methyl-S '- (2'-chlorophenyl) -3-nitro-dithiohydroquinone. A solution of <B> 150 </B> g o-chlorothiophenol, 45.7 g sodium hydroxide and 258 g 3-nitro-4-bromo-thio-anisole (m.p. 76-781)
in <B> 1150 </B> cmd abs. Ethanol is refluxed with stirring for 6 hours. After the reaction has ended, the alcohol is distilled off under reduced pressure, 500 cm3 of water are added to the residue and the mixture is extracted with 1000 cm3 of chloroform.
After washing. the chloroform solution with 400 cm3 of 1N sodium hydroxide solution and 400 cm3 of water is dried over potash and the solvent is driven off.
After the evaporation residue has been recrystallized twice from ethanol, the analytically pure S-methyl S '- (2'-chlorophenyl) -3-nitro-dithiohydroquinone with a melting point of 76 to 78 is obtained.
b) S-methyl-S '- (2'-bromophenyl) -3-nitro-dithiohydroquinone. This compound was prepared in a manner analogous to the above process from o-bromothiophenol and 3-nitro-4-chloro-thioanisole (melting point 73-751). M.p. 90-92.
c) S-methyl-S '- (2'-chlorophenyl) -3-aminodithiohydroquinone. To a boiling solution of 200 g of S-methyl-S '- (2'-chlorophenyl) -3-nitro-dithiohydroquinone (melting point 76-78) in 5 1 of methanol, a solution of 1160 g of sodium is added over 11/2 hours with stirring - Sulphide nonahydrate and 146g sodium bicarbonate in 1500 cm3 water were added dropwise and then heated to boiling for a further 12 hours.
After the reaction has ended, the methanol is evaporated off and the residue is extracted with 1500 cm3 of chloroform. The chloroform solution is washed with 300 cms of water, dried over potash and the solvent is driven off under reduced pressure. After the evaporation residue has been recrystallized twice from abs. Ethanol, the analytically pure S-methyl - S '- (2'-chlorophenyl) -3-aminodithiohydroquinone of melting point 92-94 is obtained.
d) S-methyl-S '- (2'-bromophenyl) -3-aminodithiohydroquinone.
This compound was prepared in a manner analogous to the above process from S-methyl-S '- (2'-bromophenyl) -3-nitro-dithiohydroquinone (melting point 90-92).
e) S-methyl-S '- (2'-chlorophenyl) -3-acetaminodithiohydroquinone.
A mixture of 845 g of S-methyl-S '- (2'-chlorophenyl) -3-aminodithiohydroquinone (melting point 92-94) and 354 cm 3 of acetic anhydride is refluxed for 4 hours in a 170 oil bath .
The excess acetic anhydride and the acetic acid formed are then evaporated off in vacuo and the residue is distilled in a high vacuum. The main fraction passing over at a pressure of 0.05 mm Hg of 160-170 is collected and recrystallized from ethanol. The analytically pure S-methyl-S '- (2'-chlorophenyl) -3-acetaminodithiohydroquinone melts at 89-91.
f) S-methyl-S '- (2'-bromophenyl) -3-acetaminodithiohydroquinone.
This compound was prepared in a manner analogous to the above process from S-methyl-S '- (2'-bromophenyl) -3-amno-dithiohydroquinone (melting point 115-117). M.p. 99-1011.
g) 3 methyl mercaptophenothiazine [by cyclization of S-methyl-S '- (2'-bromophenyl) -3-aminodithiohydroquinone]. A mixture of 75.0 g of S-methyl-S '- (2'-bromophenyl) -3-am @ ino-dithiohydroquinone (m.p. 115-117), 7 (1.0 g of finely powdered potassium carbonate, 2 g Copper bronze and 450 cm3 of dimethylformamide are refluxed for 15 hours with stirring at an oil bath temperature of 200 cm.
After cooling, inorganic constituents are filtered off and the filtrate is concentrated in vacuo. The evaporation residue is distilled in a high vacuum and the main fraction passing over at a pressure of 0.05 mm Hg between 190 and 200 is collected and recrystallized from ethanol. The analytically pure 3-methylmercaptophenothiazine obtained has a melting point of 138-140.
h) 3-Methylmercaptophenothiazine [by cyclization of S-methyl-S '- (2'-chlorophenyl) -3-acetantno-dithiohydroquinone]. A mixture of 66.0 g of S-methyl-S '- (2'-chlorophenyl) -3-acetaminodithiohydroquinone (m.p. 89 to 91'), 62.0 g fine. powdered potassium carbonate,
2 g of copper bronze and 450 cm3 of dimethylformamide are refluxed with stirring for 15 hours at an oil bath temperature of 200 cm. After cooling, inorganic components are filtered off and the filtrate is concentrated in vacuo. The evaporation residue is distilled in a high vacuum and the main fraction passing over at a pressure of 0.05 mm Hg between 190 and 200 is collected and recrystallized from ethanol. The analytically pure 3-methyl mercaptophenothiazine obtained has a melting point of 138-140.
Claims (1)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH175362A CH404669A (en) | 1962-02-13 | 1962-02-13 | Process for the preparation of alkyl mercapto-phenothiazine derivatives |
| FR924385A FR1458915A (en) | 1962-02-13 | 1963-02-11 | Process for preparing alkyl-mercapto-phenothiazines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH175362A CH404669A (en) | 1962-02-13 | 1962-02-13 | Process for the preparation of alkyl mercapto-phenothiazine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH404669A true CH404669A (en) | 1965-12-31 |
Family
ID=4217748
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH175362A CH404669A (en) | 1962-02-13 | 1962-02-13 | Process for the preparation of alkyl mercapto-phenothiazine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH404669A (en) |
-
1962
- 1962-02-13 CH CH175362A patent/CH404669A/en unknown
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