IL31132A

IL31132A - Azepine derivatives and processes for the production thereof

Info

Publication number: IL31132A
Application number: IL3113265A
Authority: IL
Original assignee: Geigy Ag J R
Priority date: 1964-06-26
Filing date: 1965-06-25
Publication date: 1969-07-30
Also published as: GB1087099A; IL23805A

Description

jus »»'¾>' o.'a' nn ρυτκ nnV n Azepine derivatives and processes for the production thereof J.R. GBIGY A.G Ca29312 J.R. G E I G Y A.G. BASEL 21 Isr 2006*A The present invention concerns azepine derivatives and processes for the production thereof. The compounds obtained by these processes can be used as intermediate products for the production of substances having valuable pharmacological proper-ties and also as antioxidants „ ' It has been found that compounds of the general formula I 1 wherein X represents the ethylene group -CEL-CHp- or the vinyle group -CH=CH-, represents hydrogen or a low acyl radical and represents a low alkyl group which contains more than 2 carbon atoms, if R represents hydrogen and X ethylene (-CH2-CH2-) , the phenyl group or, if R is an acyl radical, also the o- or p-nitrophenyl radical, 31132/2 # can be produced by reducing a S-acyl.lO.ll-dihydro^SH-di enz 'b,^ azepine-3-sulphonio acid chloride or the 10,11-dehydro derivative to a bis-(5-acyl-10,ll-dihydro-5H-dibenz "b,i7azepine-3-yl)-disulphide or its 10,11-dehydro compound, again reducing the latter to a 5-acyl-10,ll-dihydro-5H-dibenz!_ b,i7azepine-3-thiol or the 10,11-dehydro derivative and reaoting this in the same step with an alkylating agent or with an o- or p-nitrophenyl halide to form a 3-alkylthio- or 3-(o- or 3-(p- nitro- phenylthio)-5-aeyl^i0,ll-dihydro-5H-dibenz^ b,J*7azepine, or a 10,11-dehydro compound, reducing the 3-(o- or 3-(ρ· nitro-phenylthio)-5-aoyl-10,ll-dihydro-5H-dibenzZ b.f/azepine in the known way to the corresponding 3-(o- or 3-(p- amino- phenylthio) compound, converting this by diazotisation and reduction into the corresponding 3-phenyi-thio-5-aoyl-10,ll-dihydro-5H-dibenz/~b, 7azepine or ,11-dehydr compound, and if desired, hydrolysin the 3-alkylthio- or 3-phenylthio-5^aoyl-10,ll-dihydro-5H-dibenz ~b,j7 zepine or the 10,11-dehydro compound thereof obtained to 3-alkylthio-or 3-phenylthio- 10,ll-dihydro-5H-dibenzTb,i7azepine or the ,11-dehydro compound, or if desired, converting the 3-alkyl-or 3-phenylthio-10,ll-dihydro-5H b,j7-diazepine in the known way into the 3-alkylthio- or 3-phenyl-thio-5H-dibenzZ b,j7azepinei , In the compounds Of general formula I, as acyl radical, Rj, is preferably the acetyl radical? also R ca be, e,& another low alkanoyl radical such as the propionyl or butyryl radical or a low alkoxyoarbonyl radical such as the ethoxycarbonyl radical. As low alkyl group, is for example, the methyl, ethyl, propyl, isopropyl, nrbutyl, isobutyl and sec, butyl group.

Of the 5-acyl-10, 11-dihydro- 5H-dibenz[b,f ]azepine-3-sulphonyl chlorides used as starting materials, preferably 5-acetyl-10, 11-dihydro- H-dibenz[b, f] azepine-3-sulphonyl chloride is used; also 5-propionyl- and 5-butyryl- 10, 11-dihydro- K-dibenz[b, f ] azepine-3- sulphonyl chloride can be mentioned. These 5-acyl-lO, ll-dihydro-5H-dibe z[ b, f ] azepine-3-sulphonyl chlorides are preferably reduced with hydroiodic acid in a solvent such as glacial acetic acid to the bis- ( -acyl-lO, 11-dihydro- H-diber.z [b,f]azepine-3-yl)-disulphides. The disulphides obtained can be reduced preferably with glucose in the presence of sodium hydroxide in ethanol to 5-acyl-lO, ll-dihydro-5H-dibenz[ b, f jazepin 3-thiols which are reacted with an alkylating agent such as a low alkyl halide or dialkyl sulphate and also with an o-nitro-or p-nitro- phenyl halide in a low alkanol such as methanol or ethanol, in the same step to the 3-alkylthio- or 3-(o-nitro- or 3- (p-nitro- phenylthio) - 5~acyl-10, ll-dihydro-5H-dibenz[b, Jaze-pines. The chlorides, bromides or iodides. are used as low alkyl halides or o-nitro- and p-nitro- phenyl halides. As examples can be mentioned: methyl iodide, ethyl bromide and ethyl iodide, the propyl, isopropyl, butyl and sec butyl chlorides, bromides and iodides, o-nitro- and p-nitro- phenyl chloride and bromide. Also dimethyl or diethyl sulphate can be used as alkylating agent.

The 3- (o-nitro- or 3- (p-nitro- phenylthio) - 5-acyl--10, ll-dihydro-5H-dibenz[b> fJazepines can be preferably reduced with iron filings in dilute acetic acid or in a mineral acid such as dilute hydrochloric acid, to 3-(o-amino- or 3-(p-amino-phe ylthio)- 5-acyl-lO , 11-dihydro- H~dibenz[ b, f Jazepines and they can be diazotised and reduced in the same step. The diazotisa-tion is performed with sodium nitrite in a mineral acid such as dilute hydrochloric acid, and the diazonium salt is converted Finally, it' desired the 3-alkylthio- or 3-phenylthio- 5-acyl-10,ll-dihydro-5H~dibenz[b5 jazepines obtained can be hydrolysed with an alkali hydroxide, e.g. potassium hydroxide, preferably in a hydroxyl-containing solvent such as ethylene glycol or diethylene glycol monoethyl ether. In this way, 3-alkylthio- or 3-p.enylthio- 10,ll-dihydro-5H-dibenz[b,fJazepines are obtained, i.e. compounds embraced by formula I wherein X is the ethylene group, R is hydrogen and represents a low alkyl radical or the phenyl radical.

If desired, however, 3-alkylthio- or 3-phenylthio-5-acyl-10,ll-dihydro-5H-dibenz[b,f Jazepines can also be reacted with a brominating agent, particularly bromosuccinimide , in an inert solvent such as carbon tetrachloride, to' orm 3-alkylthio-or 3-phenylthio- 5-acyl-lO- (or 11)- bromo-10,ll-dihydro-5H-di-benz[b,f]azepines. These 3-alkylthio- or 3-phenylthio- compounds split off hydrogen bromide in the presence of an alkali hydroxide e.g. potassium hydroxide, preferably in a hydroxyl-containing solvent such as ethanol and hydrolyse in the same step to form 3-alkylthio- or 3-phenylthio- 5H-dibenz[b,f Jazepines , i.e. compounds of the general formula I wherein X is the vinylene group, R is hydrogen and R^ is a low alkyl radical or the phenyl radical.

Compounds of general formula I are obtained by a second process by diazotising 3-amino-5-acyl-10, ll-dihydro-5K-dibenz [b,f azepine in the known way to a 5-acyl-lO, ll-dihydro-5H-di~ benz[b, f] azepine-3-diazonium salt, reacting this with thiophenol in alkaline solution to form a 3-pbenylthio-5-acyl-10, ll-dihyriro-5H-dibenz[ b, f ] azepine and, if desired, hydrolysing the compound obtained to form 3-phenylthio-10, ll-dihydro-5H-dibenz[ b , ] azepine or converting it in the known v/ay into 3-phenylthio-5H-dibenz Of the 3-amino-5-acyl-10,ll-dihydro-5H-diben [b,f Jazepines which can. be used as starting materials, preferably 3-araino 5-acetyl-10,ll-dihydro-5H-dibenz[b} fJazepine is used. Also 3-amino-5-propionyl- and 3-amino-5-butyryl- 10,ll-dihydro-5H- dibenz[b,f jazepine can be used. These 3-amino-5-acyl-10, 11- dihydro-5H-dibenz[b, Jazepines are diazotised with sodium nitrite in a mineral acid, e„g. dilute hydrochloric acid, coupled in one step with thiophenol in the presence of an alkali hydroxide such as sodium hydroxide, to form diazo sulphides and converted into 3-phenylthio-5-acy1-10, 11-dihydro-5H-dibenz[b, f] azepines while splitting off nitrogen.

Finally ,' if .desired, the 3~phenylthio-5-acyl-10, 11-dihydro-5H-dibenz[b,f jazepines obtained can¾ hydrolysed with an alkali hydroxide such as potassium hydroxide, preferably in a hydroxyl-containlng solvent such as ethylene glycol or diethy-lene glycol monoethyl ether, to obtain 3-phenylthio-10 , 11-dihydro-5H-dibenz[b,f[azepine , i.e. a compound embraced by formula I wherein X is the ethylene group, R is hydrogen and is the phenyl radical.

If desired, however, the 3-phenylthio- -acyl-lO , 11-dihydro-5H-dibenz[b,f jazepines can also be reacted -with a bromina-ting agent, particularly with bromosuccinimide , in an inert solvent such as carbon tetrachloride, to form 3-phenylthio-5-acyl-10- (or 11) -bromo-10, 11-dihydro-5H-dibenz[ b, f azepi es .

These 3-phenylthio compounds split off hydrogen bromide in the presence of an alkali hydroxide such as potassium hydroxide, preferably in a hydroxyl-containlng solvent, e„g. ethanol, and hydrolyse in the same step to form 3-phenylthio- 5H-dibenz[b, Jaze-pine, i.e. a compound of general formula I wherein X is the vinylene group, R Is hydrogen and is the phenyl radical.

The following examples illustrate the production of the new compounds of general formula I and of intermediate products which have not been described hitherto but are by no means the only methods of producing same. The temperatures are given in degrees Centigrade.

Example 1 a) O g of 5-acetyl-10,ll-dihydro-5H-dibenz[b,f Jazepine- 3-sulphonyl. chloride are dissolved in 20 ml of glacial acetic acid and l8o ml of ^7% hydroiodic acid are added in small amounts The reaction mixture is left to stand for 70 hours at 20° where-half of upon/ rt fts ? solidifies. It is then poured into 2.5 litres of a % sodium thiosulphate solution and the precipitate is filtered precipitate off under suction. The brown=^-§it§¥≡-?Ss$§ms is dissolved in 1.5 litres of chloroform and extracted with 300 ml of 10% sodium thiosulphate solution. The solution thus loses its. colou „ The chloroform phase is washed with water and dried over sodium sulphate. After distilling off the chloroform in vacuo, the crude bis- ( 5-acetyl-10, ll-dihydro-5H-dibenz[ b, f ] azepine-3-yl) -disul-phide remains.

The crude product is dissolved in acetic acid ethyl ester and the solution is filtered through an aluminium oxide column (Woelm, activity I, neutral). On concentrating the filtrate in vacuo, the pure compound is obtained as an amorphous powder which decomposes at 110°. b) 12 g of sodium hydroxide in 250 ml of methanol are added dropwise to 32 g of the crude disulphide prepared according to a) and 23 g of glucose in 700 ml of ethanol, the addition being made under continuous stirring' and introduction of nitrogen. The reaction mixture is stirred for another hour at 60° and then cooled to 20°. Wo g of methyl iodide in 1 0 ml of evaporated under reduced pressure and the residue which remains is .taken up in chloroform and v/ater. The chloroform phase is washed neutral with water and dried over sodium sulphate. On evaporating the chloroform in vacuo, the crude 3-methylthio-5~ acetyl-10,ll-dihydro-5H-dibenz[b,f ]a.epine remains which is purified by distillation under high vacuum. B.P. Ί6θ°/0.003 Torr c) 99 g of the acetyl compound obtained according to 1 b) and 95 g of potassium hydroxide in 00 ml -of diethylene glycol monoethyl ether are refluxed for 8 hours. The reaction mixture is poured into 5 litres of v/ater and extracted with diethyl ether. The ether extract .is washed well with v/ater, dried oyer sodium sulphate, and concentrated in vacuo. The- residue, the 3-methylthio-10, ll-dihydro-5H-dibe z[b,f ] azepine obtained , crystallises from diethyl ether/petroleum ether, M.P. 6 °.

Example 12 a) . 3-Etiiylthio- 5-acetyl-10 , ll-dihydro-5H-dibe [ b, f ] azepine M.P. 102° from diethyl ether, is obtained analogously to 1 b) from the bis- (2-acetyl-10,ll-dihydro-5H-dibenz[b5 ]azepine-3-yl)-disulphide obtained according to la) v/ith glucose, sodium hydroxide and ethyl iodide, and b) 3-ethylthio-10, ll-dihydro-5H-dibenz[b,'t']aze ine , B.P. 15.0°/0<>001 Torr, is produced analogously, to 1 c) from the product of a) above v/ith potassium hydroxide in diethylene glycol monoethyl ether.

Example 3 a) 3-Isopropylthio- -acety1-10, ll-dihyd.ro-H-dibenz[b,f ] azepine, M.P. 89° from diethyl ether, is produced analogously to 1 b) from the bis- (5-acetyl-lO, ll-dihydro--5H-dibenz[b , f] aze-pine~3-yl)-disulphide obtained according to 1 a) with glocuse, sodium hydroxide and isopropyl bromide, and b) 3-lsopropylthio-10, ll-dihydro-5H-diben.z[bj t'Jazepine , M.P. 79° from diethyl ether/petroleum ether, is produced analogously to 1 c) from the product of a) above with potassium hydroxide in diethylene glycol monoethyl ether.

Example k a) 10 g of the disulphide obtained according to 1 a) are reduced with 6 g of glucose and 3 g of sodium hydroxide in 75 ml of methanol analogously to l b), a 0° warm solution of 15 g of 1-bromo- - nitrobenzene in 2 0 ml of ethanol is added dropv/ise to this mixture and the whole is re luxed for 12 hours The reaction product is worked up analogously to lb) and pure 3 p-nitrophenylthio- -acetyl-10, ll-dihydro- 5 I-dibenz[b,f]a¾e ine is obtained, M.P. 126° from ethanol. b) 8.0 g of the thioether obtained according to a) are dissolved in 100 ml of glacial acetic acid and the solution is heated to 90-95°· 15 ml of water are added to this solution while stirring .well and 10 g of- iron filings are added in small portions. Another 15 nil of water are then added, the reaction mixture is stirred for 1 hour at 90-95°> 500 ml of water are th added and it is extracted with diethyl ether. The ether phase is 'washed with saturated sodium carbonate solution and water, dried over sodium sulphate and concentrated. 1 g of sodium nitrite are added to the residue in 200 ml of water and 30 ml of concentrated hydrochloric acid at 0° and the whole is stirre-for half an hour at 0-5°. 30 ml of cold hypophosphorous acid are then added and the reaction mixture is left to stand, first for 12 hours at 0° and then for 12 hours at 20°. It is then extracted with diethyl ether. The ether solution is extracted with 2N hydrochloric acid, washed neutral with saturated sodium bicarbonate solution and water, dried over sodium sulphate and dibenz[b, jazepine is obtained, M.P. 110-111°, c) 25.2 g of 3-amino-5-acetyl~10,ll-dihydro-5H-dibenz[b,f ] azepine are' dissolved in 25 ral of concentrated hydrochloric acid and 230 ml of water. The solution is cooled in an ice bath to 0° and 7. of sodium nitrite in 20 ml of water are added in small portions. The diazonium salt solution obtained is then added dropwise to 12 g of thiophenol in 200 ml of 20 sodium hydroxide solution which have been placed in a stirring flask and kept at 73-75°· In order to avoid too high a concentration of the diazo sulphide formed as intermediate, the development of nitrogen is quantitatively followed during the reaction.

On completion of the dropwise addition of the diazonium salt solution, the reaction mixture' is heated or 30 minutes at 90 and after cooling to 20°, it is extracted with chloroform. The chloroform phase is washed well with 2 sodium hydroxide solution, 2N hydrochloric acid and water, dried over sodium sulphate and concentrated in vacuo. The residue, the 3-phenylthio- -acetyl-10, ll-dihydro-5H-dibenz[b,f] azepine obtained, crystallises from diethyl ether/petroleum ether, M.P. 112°. d) 8.5 g of the 3-phenylthio- -acetyl-lO, ll-dihydro-5H-diben¾[b, Jazepine produced according to b) or c), 7 g of potassium hydroxide and 100 ml of diethylene glycol monoethyl ether are refluxed for 12 hours. The reaction mixture is then worked up analogously to 1 c) whereupon 3-phenylthio-10, 11-dihydro-5H-dibenz[b,f jazepine, Μ.Ρ.· 101° from diethyl ether/ petroleum ether, is obtained. a) 10 g of 3-araino-5-acetyl-5H-dibenz[b, f jazepine are dissolved in 20 ml of concentrated hydrochloric acid and 80 ml of water, and the solution is cooled in an ice bath to 0°. 2.8 g of sodium nitrite dissolved in 10 ir.l of water are added in small portions to the ice cooled reaction solution over a period of 40 minutes. The diazoniura salt solution is then added to 300 ml of glacial acetic acid to which 1.2 g of copper- (II) chloride has been added and which has been saturated with sulphur dioxide. Sulphur dioxide is then introduced for 2 hours. The reaction mixture is poured into 1.5 litres of ice water whereupon the chlorosulphonyl compound crystallises. It is filtered off, dissolved in benzene and washed with sodium bicarbonate and water. After distilling off the benzene , 3-chlorosulphonyl-5 -acetyl-5H-dibenz [b, f ]azepine remains as an amorphous mass. b) This chlorosulphonyl compound is reduced with hydro-iodic acid as described in Example 1. The amorphous bis- (5-a'cetyl-5H-dibenz[b, f ]azepin-3-yl) disulphide without further purification is converted with glucose, sodium hydroxide and methyl iodide into 3-methylthio-5-acetyl-5H-dibenz[b,f Jazepine. 3-Methylthio-5H-dibenz[b, f jazepine is produced therefrom, with potassium hydroxide in diethylene glycol monoethyl ether. After recrystallisation from acetone, it melts at 168ΰ.

Example 6 In an analogous manner to Example 1 bis (5-acetyl-5H-dibenz- [b , f ]azepine-3-yl) disulphide is reacted with glucose, sodium hydroxide and ethyl bromide to 3-ethylthio-5-acetyl-5H-dibenz-[b,f jazepine from which, after saponification 3-ethyl~thio-5H-dibenz [b , f jazepine is obtained from ether/petroleum ether; M.P. 143°.

Claims

What we claim is:

1. New azepine derivatives of the general formula I

wherein X represents the ethylene (-CP^-CI^-) or vinylene

(-CH=CH-) group,

R represents hydrogen or a low acyl radical and

R- represents a low alkyl group which contains more

2 carbon atoms if R represents hydrogen and X ethylene

(-CH2-CH2-), the phenyl group or, if R is an acyl

radical, also the o- or p_-nitrophenyl radical.

2. 3-Ethylthio-5-acetyl-10 , ll-dihydro-5H-dibenz [b , f Jazepine .

3. 3-Isopropylthio-5-acetyl-10 , ll-dihydro-5H-dibenz [b , f ]azepine .

. 3-Phenylthio-5-acetyl-10 , ll-dihydro-5H-dibenz [b , f jazepine .

5. 3-Methylthio-5H-dibenz [b , f ]azepine .

6 · 3-Ethylthio-5H-dibenz [b , f ]azepine .

7. 3-Isopropylthio-10 , ll-dihydro-5H-dibenz [b , f ]azepine .

8. 3-Phenylthio-10 , ll-dihydro-5H-dibenz [b , f Jazepine .

9. Process for the production of azepine 'derivatives of the general formula I

n

V

wherein X represents the ethylene group (-CI^-CK^-) or the vinylene

group (-CH=CH-) ,

R represents hydrogen or a low acyl radical, and

represents a low alkyl group which contains more than 2

carbon atoms, if R represents hydrogen and X ethylene

(-CHp-Cl^-) , the phenyl group or, if R is the acyl radical, also the o- or p- nitro-phenyl radical, characterised by reducing a 5-acyl-lO, ll-dihydro-5H-dibenz [b , f ]azepine-3-sulphonic acid chloride or the 10, 11-dehydro derivative to a bis-(5-acyl-10 , ll-dihydro-5H-dibenz [b , f ]azepine-3-yl) -disulphide , or its

10 , 11-dehydro compound, further reducing the compounds thus

obtained to a 5-acyl-10 , ll-dihydro-5H-dibenz [b , f ]azepine-3-thiol or the 10 , 11-dehydro derivative, and reacting this in the same step with an alkylating agent or with an o- or p-nitrophenyl halide to form a 3-alkylthio- or 3-(o- or 3-(p- nitro-phenylthio) -5-acyl-10 , ll-dihydro-5H-dibenz [b , f ]azepine or a 10 , 11-dehydro compound, reducing in a manner known for reducing a 3-(o-nitro- or 3-(p-nitro-phenylthio) -5-acyl-10 , ll-dihydro-5H-dibenz [b , f ]azepine or the

10 , 11-dehydro derivative thereof to the corresponding 3-(o-amino-or 3-(p-amino- phenylthio) compound, converting this by diazotisa-tion and reduction into the corresponding 3-phenylthio-5-acyl-lo, 11-dihydro-5H-dibenz [b , f ]azepine or the 10 , 11-dehydro derivative thereof and, if desired, hydrolysing the 3-alkylthio- or 3-phenylthio- 5-acyl-10 , ll-dihydro-5H-dibenz [b , f Jazepine or the 10 , 11-dehydro

compound obtained to 3-alkylthio- or 3-phenylthio- 10 , 11-dihyd o-SH-dibenz [b , f ]azepine or its 10 , 11-dehydro derivative, or, if desired, converting in a manner known for converting a 3-alkylthio- or 3-phenylthio-10 , ll-dihydro-5H-dibenz [b , f jazepine into a 3-alkylthioT or 3-phenylthio-5H-dibenz [b , f ]azepine .

31132/2

10. Process for the preparation of compounds of formula I as defined in olaim 1 in whloh ^ IB phenyl } characterised by diazotising in a manner known for diazotising a 3-amino-5-acyl-10,ll-dihydro-5H-dibenz-i "b»i7azepin9 ±nto a 5-acyl-lO,11* aihydro-SH-diben^-b.^a.epine- diazonium .alt, reacting this with thiophenol in alkaline solution to form a 3*phenylthio-5-acyl-10,H-dihydro-5H-dibenzf*bt)l7a)sepine and, if desired, hydrolysing the compound obtained to 3-phenylthio-10,ll- or converting in a manner known

for converting a 3-phenylthio-10,ll-dihydro-5H-dibenz *"b,l azepine into a 3-phenyl-5H-dlbenz , b,,f7azeplne.

11. New azepine derivatives of the general formula I defined in olaim 1 substantially as hereinbefore described with reference to any of Examples 1 to 5·

12. New azepine derivatives of the general formual I defined in claim 1; substantially as hereinbefore described with re erence to Example 6.