SI8911372A8 - Process for preparing new intermediate usable in process for preparing oxo compounds - Google Patents

Description

Postopek za pripravo novega intermediata, uporabnega v postopku za pripravo okso spojineA process for the preparation of a new intermediate useful in the process for the preparation of an oxo compound

Področje tehnike, v katero spada izumFIELD OF THE INVENTION

Izum je s področja organske kemijske sinteze in se nanaša na postopek za pripravo 5-ciano-10-nitro-5H-dibenz/b,f/azepina s formuloThe invention relates to the field of organic chemical synthesis and relates to a process for the preparation of 5-cyano-10-nitro-5H-dibenz / b, f / azepine of the formula

azepina s formulo III.azepine of formula III.

ki ga lahko uporabimo v novem in tehnično naprednem postopku za pripravo 5-karbamoil-10-okso-10,11-dihidro-5H-dibenz/b,f/2which can be used in a new and technically advanced process for the preparation of 5-carbamoyl-10-oxo-10,11-dihydro-5H-dibenz / b, f / 2

Celoten postopek za pripravo 5-karbamoil-10-okso-10,11dihidro-5H-dibenz/b,f/azepina predstavlja naslednja reakcijska shema.The following reaction scheme is a complete process for the preparation of 5-carbamoyl-10-oxo-10,11 dihydro-5H-dibenz / b, f / azepine.

ΨΨ

Tehnični problemA technical problem

Obstajala je potreba, da bi po tehnološko ugodnem postopku pripravili nov intermediat za tehnično naprednejšo pripravo okso spojine s formulo III.There was a need to prepare a new intermediate for the more technically advanced preparation of the oxo compound of Formula III by a technologically advantageous process.

Stanje tehnikeThe state of the art

Intermediati s formulo (II) so nove spojine in zato postopki zanje ne obstajajo.The intermediates of formula (II) are novel compounds and therefore no processes exist for them.

Opis rešitve tehničnega problema z izvedbenimi primeriDescription of solution to a technical problem with implementation examples

Postopek izvedemo tako, da nitriramo 5-ciano-5H-dibenz /b,f/azepin s formulo IThe process is carried out by nitrating 5-cyano-5H-dibenz / b, f / azepine of formula I

Dobljeni 5-ciano-10-nitro-5H-dibenz/b,f/azepin s formulo II lahko nato hidroliziramo v 5-karbamoil-10-nitro-5H-dibenz/b,f/ azepin s formulo IV, v tem reduciramo 10-nitro skupino, redukcijski proizvod hidroliziramo in 5-karbamoil-10-okso-10,11-dihidro-5H-dibenz/b,f/azepin izoliramo v čisti obliki.The resulting 5-cyano-10-nitro-5H-dibenz / b, f / azepine of formula II can then be hydrolyzed to 5-carbamoyl-10-nitro-5H-dibenz / b, f / azepine of formula IV, thereby reducing 10 -nitro group, the reducing product is hydrolyzed and 5-carbamoyl-10-oxo-10,11-dihydro-5H-dibenz / b, f / azepine is isolated in pure form.

Nitriranje spojine I v spojino s formulo II v smislu izuma poteče s pomočjo didušikovega trioksida (^0^), .v danem primeru v zmesi s kisikom, npr. zrakom, ali s pomočjo didušikovega tetroksida (NgO^) ali zmesi takih spojin, poleg tega pa tudi s pomočjo solitrove kisline. Presnovo izvedemo v nižjih alkankarboksilnih ali halogennižjialkankarboksilnih kislinah z vsakokrat do 4 atomi ogljika, kot je npr. ocetna, propionova, n-maslena ali izomaslena kislina, nadalje npr. trifluor- ali triklorocetna kislina, v danem primeru v zmesi z vodo, ali v njihovih anhidridih, kot so npr. anhidrid ocetne, propionove, n-maslene, izomaslene ali trifluorocetne kisline, ali v zmeseh takih karboksilnih kislin z ustreznimi anhidridi. Po prednostni izvedbeni ob- 4 liki postopka v smislu izuma uporabimo kot topila anhidride navedenih nižjih alkankarboksilnih kislin, npr. acetanhidrid, v danem primeru v zmesi z nižjoialkahkarboksilno kislino, npr. ocetno kislino.The nitration of compound I to the compound of formula II of the invention proceeds by means of nitrous trioxide (^ O), optionally in admixture with oxygen, e.g. air, or with the help of nitrous oxide (NgO ^) or a mixture of such compounds, and also with the aid of nitric acid. The reaction is carried out in lower alkanecarboxylic or halogenoalkanecarboxylic acids with up to 4 carbon atoms each, such as e.g. acetic, propionic, n-butyric or isobutyric acid, further e.g. trifluoro- or trichloroacetic acid, optionally in admixture with water, or in their anhydrides, such as e.g. acetic anhydride, propionic, n-butyric, isobutyric or trifluoroacetic acids, or in mixtures of such carboxylic acids with the corresponding anhydrides. According to a preferred embodiment, the process of the invention is used as solvents for the anhydrides of said lower alkanecarboxylic acids, e.g. acetanhydride, optionally in admixture with lower alkali carboxylic acid, e.g. acetic acid.

Razmerje izhodne snovi glede na uporabljeno količino topila (teža/volumen) lahko variira v širokih mejah. S pridom uporabimo razmerje izhodne snovi proti topilu v območju od 1:5 do 1:5θ· Reakcijska temperatura je v območju od okoli 0 do 120°, zlasti 40 do 80°.The ratio of starting material to the amount of solvent used (weight / volume) can vary within wide limits. The ratio of the starting material to the solvent is advantageously used in the range from 1: 5 to 1: 5θ · The reaction temperature is in the range from about 0 to 120 °, especially 40 to 80 °.

Po Chemical Reviews 56. (1945), str. 211 do 212, dobijo s presnovo stirola z dušikovim trioksidom zmes nitrozo in nitro spojin. Poleg tega vodi presnovni proizvod stirola z dušikovim trioksidom do 1-nitro-2-feniletilena, če reakcijski proizvod podvržejo destilaciji z vodno paro. Nadalje je tam navedeno, da vodi presnova stilbena z dušikovim tetroksidom do 1,2-dinitro-l,2-difeniletra. Po strani 218 iste literature daje presnova cikloheksena s suhim dušikovim tetroksidom v hladnem petroletru ustrezen bis-nitrozo-nitro^derivat in oljnate stranske proizvode.According to Chemical Reviews 56. (1945), p. 211 to 212 are obtained by the reaction of styrene with nitrogen trioxide a mixture of nitroso and nitro compounds. In addition, the metabolic product of styrene with nitrogen trioxide leads to 1-nitro-2-phenylethylene if the reaction product is distilled with water vapor. It is further stated that the metabolism of stilbene with nitrogen tetroxide leads to 1,2-dinitro-1,2-diphenylether. According to page 218 of the same literature, the reaction of cyclohexene with dry nitrogen tetroxide in cold petroleum ether gives the corresponding bis-nitroso-nitro ^ derivative and oily by-products.

V J.Org.Chem. 28, (1965), str. 125 do 129, je navedeno da presnovni proizvod olefina z didušikovim tetroksidom v bi stvu vsebuje nitro in nitrozo skupine, katerega pretvorba v nitro-olefinsko spojino zahteva dodatek trietilamina. Tako npr. presnovijo ciklookten z didušikovim tetroksidom in natoIn J.Org.Chem. 28, (1965), p. 125 to 129, it is stated that the metabolite product of olefin with nitrous tetroxide contains nitro and nitroso in the group whose conversion to the nitro-olefin compound requires the addition of triethylamine. So e.g. metabolize cyclooctene with nitrous nitroxide and then

- 5 reakcijski proizvod obdelajo s trietilaminom, nakar dobijo 1ni troc iklookten.- 5 the reaction product is treated with triethylamine to give 1-tronic iklooctene.

V nasprotju s tem smo presenetljivo ugotovili, da pri nitriranju v smislu izuma odpadejo dodatne operacije, kot npr. destilacija z vodno paro ali obdelava reakijske zmesi s trietilaminom, in da silno enostavna obdelava vodi do vseskozi dobrih dobitkov nitro spojine s formulo II. Ta spojina je nova_: in v literaturi ni opisana.In contrast, it has surprisingly been found that the nitration process of the invention does not require additional operations such as e.g. distillation with water vapor or treatment of the reaction mixture with triethylamine, and that a very simple treatment leads to all-time good yields of the nitro compound of formula II. This compound is novel _: and has not been described in the literature.

Za pretvorbo dobljeaečspojine:slformulo II v v spojino s formulo III spojino s formulo II lahko hidroliziramo s pomočjo kislih sredstev, npr. kot so navedena, kot npr. z borovim trifluoridom v ocetni kislini, v danem primeru v prisotnosti nadaljnjega inertnega topila, npr. topila aromatskega značaja, kot klorbenzola, v prisotnosti vode, in spojino s formulo IV, ki jo vsebuje reakcijska zmes, nato, ne da bi jo izolirali, reduciramo^kot jebOo npr. naveden} npr. s pomočjo katalitsko aktiviranega vodika, kot vodika v prisotnosti hidrimega katalizatorja, kot nikljevega katalizatorja ali katalizatorja plemenite kovine, npr. Baneyevega niklja ali katalizatorja paladija na oglju, ali z nascent6 nim vodikom, npr. kot smo navedli, npr. z železom v Tri κΉη-ί ₃ npr. mineralni kislini, npr. vodni solni ki ni in-i _> ali nižji alkankarboksilni kislini ali balogennižjialkankarboksilni kislini, npr. kot smo navedli, npr. ocetni kislini, ali z zmesjo BF,,-ocetna kislina-voda, ki je že prisotna v reakcijskem nastavku. Redukcijski proizvod, ki se nahaja v reakcijski zmesi, brez nadaljnjega izoliranja nato ali tudi istočasno hidroliziramo s pomočjo kislega sredstva, npr. kot smo navedli, npr. s pomočjo vodne kisline, npr. zmesi BF^-očetna kislina-voda, ki se nahaja v reakcijski zmesi., in nastali končni proizvod s formulo III izoliramo v čisti , obl ik-i,.For the conversion of the compound obtained: Formula II into a compound of formula III, a compound of formula II can be hydrolyzed by acidic agents, e.g. as listed, e.g. with boron trifluoride in acetic acid, optionally in the presence of a further inert solvent, e.g. solvents of an aromatic nature, such as chlorobenzene, in the presence of water, and the compound of formula IV contained in the reaction mixture, is then reduced, without isolation, as in e.g. specified} e.g. using catalytically activated hydrogen, such as hydrogen in the presence of a hydride catalyst, as a nickel catalyst or a precious metal catalyst, e.g. Baney nickel or palladium catalyst on charcoal or with concentrated hydrogen, e.g. as stated, e.g. with iron in Tri κΉη-ί ₃ e.g. mineral acids, e.g. aqueous salt which is not _in-i> or a lower alkanecarboxylic acid or balogennižjialkankarboksilni acid, for example. as stated, e.g. acetic acid, or with a mixture of BF ,, - acetic acid-water already present in the reaction sequence. The reduction product contained in the reaction mixture is subsequently or simultaneously hydrolyzed by an acidic agent, without further isolation, e.g. as stated, e.g. by means of aqueous acid, e.g. mixtures of BF ^ -acetic acid-water contained in the reaction mixture., and the resulting final product of formula III is isolated in pure, obl.

Alternativno lahko v spojinah s formulo II reduciramo 10-nitro skupino, redukcijski proizvod hidroliziramo, vmesni 5-ciano-10-okso-T0,11-dihidro-5H-dibenz/b,f/azepin s formulo V lahko izoliramo in nato hidroliziramo. Ta // varianta postopka v smislu izuma obstoji v tem, da spojino s formulo II pretvorimo v spojino s formulo V in iz tega pripravimo končni proizvod s formulo III. Torej v 5-ciano10-nitro-5H-dibenz[b,f]azepinu s formulo II nitro skupino reduciramo po eni od zgoraj opisanih metod in v reakcijski zmesi nastali vmesni proizvod s pomočjo hidrolize prevedemo v spojino s formulo V. Redukcijo lahko izvedemo, kot smo že prej navedli, na primer s pomočjo katalitsko aktiviranega vodika, kot vodika v prisotnosti hidrimega katalizatorja, npr. nikljevega katalizatorja ali katalizatorja plemenite kovine, npr. Raneyevega niklja ali katalizatorja paladija na oglju, v primernem topilu, npr. nižjem alkanolu z do 4 atomi ogljika, npr. metanolu ali etanolu, ali s pomočjo nascentnega vodika, npr. s pomočjo primerne kovine, kot v danem primeru amalgamiranega cinka ali zlasti železa v kislini, npr. mineralni kislini, kot razredčeni žveplovi ali koncentrirani solni kislini, ali nižjialkankarboksilni kislini, npr. eni od zgoraj navedenih, npr. ocetni kislini, ali s pomočjo kemičnega redukcijskega sredstva, kot npr. kositrovega(II) klorida.22^0. Pri tem lahko uporabimo dodatna topila, npr. nižjijalkanol z 1 do 4 atomi ogljika, npr. etanol, ali nižjialkoksinižjialkanol z vsakokrat do 4 atomi ogljika v nižjem alkoksilnem in nižjem alkanolnem delu, npr. 2-metoksiali 2-e t oksi etanol, in/ali topilo aromatskega značaja, npr. v danem primeru nižjialkiliran, kot metiliran, ali halogeniran, kot kloriran,benzol, kot benzol, toluol, ali klorbenzol. Reakcijska temperatura je v območju 10 do 100°, prednostno 3θ do ?0°. Reakcijsko zmes nato, smotrno po odstranitvi netopnih deležev, podvržemo hidrolizi, npr. učinkovanju vode, in po obdelavi izoliramo 5-ciano-10-okso-10,11— dihidro-5H-dibenz[b,f3 azepin s formulo V v čisti obliki, ki ga dobimo z dobrim dobitkom in odlično čisto to. Ta spojina je nova in v literaturi ni opisana. Prednostna izvedbena oblika opisane pretvorbe spojine s formulo II v spojino s formulo V obstoji v tem, da za redukcijo s pomočjo kovine, npr. železa, kot je zgoraj opisano, uporabimo topilo, ki nastale kovinske soli, npr. železove soli, topi in tako v veliki meri prepreči’ nastanek težko filtrabilne oborine, npr. v obliki blata. Taka topila so npr. močno polarna organska topila, npr. nižjijalkiletri etilenglikola, kjer ima nižjijalkil do 4 atome ogljika in predstavlja npr. metil ali etil, in je torej npr. etilenglikol-monoetilester.Alternatively, a 10-nitro group can be reduced in the compounds of formula II, the reducing product hydrolyzed, an intermediate 5-cyano-10-oxo-T0,11-dihydro-5H-dibenz / b, f / azepine of formula V can be isolated and then hydrolyzed. This // variant of the process according to the invention consists in converting a compound of formula II into a compound of formula V, from which a final product of formula III is prepared. Thus, in the 5-cyano10-nitro-5H-dibenz [b, f] azepine of formula II, the nitro group is reduced by one of the methods described above, and the resulting intermediate is converted by hydrolysis into a compound of formula V. The reduction can be carried out, as previously stated, for example by means of catalytically activated hydrogen, as hydrogen in the presence of a hydride catalyst, e.g. Nickel or precious metal catalyst e.g. Raney nickel or palladium catalyst on charcoal, in a suitable solvent, e.g. lower alkanol with up to 4 carbon atoms, e.g. methanol or ethanol, or using nascent hydrogen, e.g. using suitable metal, such as in the case of amalgamated zinc, or in particular iron in acid, e.g. mineral acids, such as dilute sulfur or concentrated hydrochloric acid, or lower alkanecarboxylic acid, e.g. one of the above, e.g. acetic acid, or by means of a chemical reducing agent, such as e.g. of tin (II) chloride.22 ^ 0. Additional solvents may be used, e.g. lower alkanol of 1 to 4 carbon atoms, e.g. ethanol, or lower alkoxysilane alcohol with up to 4 carbon atoms each in the lower alkoxyl and lower alkanol moieties, e.g. 2-methoxyali 2- ethoxy ethanol, and / or an aromatic solvent, e.g. optionally lower alkylated, such as methylated or halogenated, such as chlorinated, benzene, such as benzene, toluene, or chlorobenzene. The reaction temperature is in the range of 10 to 100 °, preferably 3θ to? 0 °. The reaction mixture is then hydrolyzed, e.g. after removal of the insoluble moieties, e.g. water, and after treatment, 5-cyano-10-oxo-10,11-dihydro-5H-dibenz [b, f3 azepine of formula V is isolated in pure form, obtained in good yield and excellent clean. This compound is novel and has not been described in the literature. A preferred embodiment of the described conversion of a compound of formula II into a compound of formula V is that for reduction by metal, e.g. iron, as described above, use the solvent formed metal salts, e.g. iron salts, melts and thus largely prevents the formation of a difficult filtration precipitate, e.g. in the form of mud. Such solvents are e.g. strongly polar organic solvents, e.g. lower alkylethyl ethers of ethylene glycol, wherein the lower alkyl has up to 4 carbon atoms and represents e.g. methyl or ethyl, and is e.g. ethylene glycol monoethyl ester.

Nato cianojskupino v spojini s formulo V pretvorimo v karboksamidno skupino končnega proizvoda s formulo III s pomočjo hidrolize. To lahko izvedemo s pomočjo bazičnih ali kislih sredstev. Kot bazična sredstva pridejo za to v poštev npr. p oksidi ali hidroksidi zemelj skoalkali jskih ali alkalijskih kovin, npr. magnezijev ali kalcijev hidroksid, nadalje npr. natrijev hidroksid, v danem primeru v prisotnosti peroksida, kot vodikovega peroksida, ali alkalijskega bikarbonata, kot natrijevega bikarbonata, v zmesi z vodikovim peroksidom, medtem ko kisla sredstva predstavljajo npr. mineralne kisline, kot žveplova ali polifosforjeva kislina, nadalje nižjefalkankarboksilne ali halogennižjialkankarboksilne kisline z do 4 atomi ogljika, npr. mravljinčna ali ocetna kislina oz. triklor- ali trifluorocetna kislina v zmesi z mineralnimi kislinami, npr. koncentrirana žveplova kislina. Kisla sredstva so nadalje Lewisove kisline, npr. borovjbrifluorid, ki je lahko raztopljen v nižji/alkankarboksilni kislini «zgoraj opisane vrste, kot ocetni kislini, je pa lahko tudi definirana spojina, npr. s formulo Bk^.2 CH^COOH. V danem primeru dodamo reakcijski zmesi še nadaljnje topilo, npr. topilo aromatskega značaja, kot npr. klorbenzol. Reakcijske temperature so v ob moč ju od -5 čLo +15θ°, prednostno 0 do 40°.The cyano group in the compound of formula V is then converted to the carboxamide group of the finished product of formula III by hydrolysis. This can be done using basic or acidic agents. As basic assets, for example, they are suitable. p oxides or hydroxides of earth alkaline or alkali metals, e.g. magnesium or calcium hydroxide, further e.g. sodium hydroxide, optionally in the presence of peroxide, such as hydrogen peroxide, or alkali bicarbonate, such as sodium bicarbonate, in admixture with hydrogen peroxide, while the acidic agents are e.g. mineral acids such as sulfuric or polyphosphoric acid, further lower -alkanecarboxylic or halogenated-lower-carboxylic acids with up to 4 carbon atoms, e.g. formic or acetic acid, respectively. trichloro- or trifluoroacetic acid in admixture with mineral acids, e.g. concentrated sulfuric acid. Acidic agents are further Lewis acids, e.g. boronbrifluoride, which may be dissolved in the lower / alkanecarboxylic acid "of the species described above, as acetic acid, but may also be a defined compound, e.g. with the formula Bk ^ .2 CH ^ COOH. In the present case, a further solvent is added to the reaction mixture, e.g. a solvent of an aromatic character, such as e.g. chlorobenzene. The reaction temperatures are in the range of -5 ° Lo + 15θ °, preferably 0 to 40 °.

Naslednji primeri služijo kot ilustracija izuma; temperature so v stopinjah Celzija.The following examples serve to illustrate the invention; temperatures are in degrees Celsius.

PRIMER 1EXAMPLE 1

6,0 g (0,027 molov) 5-ciano-5H-dibenz[b,fJazepina raztopimo v zmesi 80 ml acetanhidrida in 20 ml ocetne kisline. Segrejemo na 50° in po kapljicah 1 1/2 ure dodajamo raztopine 5,6 g (0,08 molov) natrijevega nitrita v 10 ml vode, pri čemer ne pustimo, da bi temperatura narasla nad 55°. Še 2 uri držimo pri 5°° in nato topilo oddestiliramo pri zmanjšanem pritisku in temperaturi kopeli 50°. Ostanek 2-krat digeriramo s po 100 ml ledene vode in prevzamemo v 80 ml etanola. Po večurnem stanju pri 0° odsesamo izločene rumene kristale in izperemo z malo etanola. Dobljeni 5-ciano-10-nitro-5H-dibenz[b,fJazepin se tali pri 175 do 176° ob razpadu.6.0 g (0.027 mol) of 5-cyano-5H-dibenz [b, f] is dissolved in a mixture of 80 ml of acetanhydride and 20 ml of acetic acid. Heat to 50 [deg.] And a solution of 5.6 g (0.08 mol) of sodium nitrite in 10 ml of water is added dropwise over 1 1/2 hours without allowing the temperature to rise above 55 [deg.]. The mixture is kept at 5 °° for 2 hours and then the solvent is distilled off under reduced pressure and a bath temperature of 50 °. The residue was digested twice with 100 ml of ice water each and taken up in 80 ml of ethanol. After an evening condition at 0 °, suction off the separated yellow crystals and wash with little ethanol. The resulting 5-cyano-10-nitro-5H-dibenz [b, fJazepine melts at 175 to 176 ° on decay.

Dobitek: 5,2 g, 72 % teor.Yield: 5.2 g, 72% of theory.

Analitski in spektroskopski podatki so v skladu z domnevano strukturo.The analytical and spectroscopic data are consistent with the assumed structure.

PRIMER 2EXAMPLE 2

6,5 g (θ,θ5 mole) 5-ciano-5H-dibenz[b,fJazepina raztopimo v zmesi 100 ml ocetne kisline in 100 ml acetanhidrida. Segrejemo na 40° in 45 minut dodajamo 6,2 g (0,09 molov) natrijevega nitrita, pri čemer skozi raztopino vodimo počasen zračni tok. Temperatura naraste brez nadaljnjega segrevanja na 55° in jo po koncu dodajanja nitrita še 1 uro držimo na 55 .6.5 g (θ, θ5 moles) of 5-cyano-5H-dibenz [b, f] are dissolved in a mixture of 100 ml of acetic acid and 100 ml of acetanhydride. Heat to 40 ° C and add 6.2 g (0.09 mol) of sodium nitrite for 45 minutes, allowing a slow air flow through the solution. The temperature rises without further heating to 55 ° C and is kept at 55 for one hour after nitrite is added.

Topilo oddestiliramo v vakuumu pri temperaturi kopeliThe solvent was distilled off in vacuo at bath temperature

50°, prevzamemo ostanek v 300 ml toluola, stresamo za odstra nitev anorganskih, sestavin večkrat z vodo in toluol oddestiliramo v vakuumu do 40 ml. Izločeni rumeni proizvod odsesamo in izperemo z malo toluola; identičen je s 5-ciano-10-nitro5H-dibenz[b,f]azepinom po primeru 1.50 °, the residue is taken up in 300 ml of toluene, shaken to remove inorganic, constituents repeatedly with water and the toluene distilled off in vacuo to 40 ml. The extracted yellow product is sucked off and washed with a little toluene; it is identical to 5-cyano-10-nitro5H-dibenz [b, f] azepine according to Example 1.

Dobitek: 6,1 g; 77»5 % teor.Yield: 6.1 g; 77 »5% Theor.

PRIMER 3EXAMPLE 3

19,6 g (0,09 molov) 5-ciano-5H-dibenzEb,f]azepina presnovimo kot v primeru 2 v 300 ml ocetne kisline in 300 ml acetanhidrida z 18,6 g (0,27 molov) natrijevega nitrita-Rdeče rumeni sirup, dobljen po odparjenju topila, premešavamo s 3OO ml vode do popolne strdit ve. Odsesamo, izperemo z vodo do nevtralne reakcije filtrata in posušimo v vakuumu.19.6 g (0.09 mol) of 5-cyano-5H-dibenzEb, f] azepine were reacted as in Example 2 in 300 ml of acetic acid and 300 ml of acetanhydride with 18.6 g (0.27 mol) of sodium nitrite-Red. The yellow syrup obtained after evaporation of the solvent is mixed with 3OO ml of water until complete solidification. Suction off, rinse with water to neutralize the filtrate and dry in vacuo.

Isti surovi proizvod dobimo, če gornjo presnovo izvedemo pri temperaturi 80 do 85°.The same crude product is obtained if the above metabolism is carried out at a temperature of 80 to 85 °.

Dobljeni surovi proizvod je primeren za nadaljnje presnove, lahko pa ga očistimo tudi takole:The obtained crude product is suitable for further metabolism, but can also be purified as follows:

1. 23»7 g surovega proizvoda prekristaliziramo iz izopropanola in dobimo rumen kristalni material, ki je identičen s 5-ciano-lO-nitro-5H“dLbenz[b,f]azepinom po primeru 1. Dobitek 18,0 g, 76,2 % teor.1. 23 "7 g of crude product was recrystallized from isopropanol to give a yellow crystalline material identical to 5-cyano-10-nitro-5H" dLbenz [b, f] azepine according to Example 1. Yield 18.0 g, 76. 2% theor.

2. Končni proizvod, ki je enak glede na dobitek in kvaliteto dobimo z digeriranjem surovega proizvoda z ocetno kislino2. The final product, which is the same in terms of yield and quality, is obtained by digesting the crude product with acetic acid.

PRIMER 4EXAMPLE 4

V buči proizvedemo s počasnim dokapa van jem 20 %-ne žveplove kisline v koncentrirano vodno raztopino 40,0 g (0,58 molov) natrijevega nitrita nitrozne pline (NgOj), ki jih s počasnim zračnim tokom uvedemo v raztopino 10,9 g (0,05 molov) 5-ciano-5H-dibenzLb,f]azepina v 100 ml toluola, segreto na 55°. Koncentracijo dovedenega zračnega kisika pri tem vzdržujemo tako nizko, da se ne morejo tvoriti eksplozijske zmesi toluolne pare-kisika. Uvajamo do popolne presnove izhodnega materiala (kontrola s tenkoslojno kromatografijo), prebitek U^O^ preženemo z živahni m tokom dušika in toluol odparimo pod zmanjšanim pritiskom pri temperaturi 40°. Dobljeni rdeči sirup prevzamemo v 100 ml izopropanola. Po večurnem stanju pri 5° kristalizat odsesamo in izperemo z malo izopropanola. Dobljeni 5-ciano-10-nitro-5U-dibenz[b, f]azepin je identičen s proizvodom po primeru 1.In the flask, 20% of sulfuric acid is slowly added to a concentrated aqueous solution of 40.0 g (0.58 mol) of sodium nitrite nitrous gas (NgOj), which is introduced into a solution of 10.9 g (by slow air flow). 0.05 mol) of 5-cyano-5H-dibenzylb, f] azepine in 100 ml of toluene, heated to 55 °. At the same time, the concentration of the supplied air oxygen is kept so low that no explosive mixtures of toluene vapor-oxygen can form. Introduce to the complete metabolism of the starting material (control by thin layer chromatography), excess U ^ O ^ is trapped with a live m nitrogen stream and the toluene is evaporated under reduced pressure at 40 °. The resulting red syrup is taken up in 100 ml of isopropanol. After an evening condition at 5 °, the crystallizate is sucked off and washed with a little isopropanol. The resulting 5-cyano-10-nitro-5U-dibenz [b, f] azepine is identical to the product of Example 1.

Dobitek: 9,4 g, 71,7 % teor.Yield: 9.4 g, 71.7% of theory.

PRIMER 5EXAMPLE 5

Analogno načinu dela, opisanemu v primeru 4, proizvedemo v buči iz 55,o g (0,8 molov) natrijevega nitrita nitroz ne pline in jih vodimo s pomočjo počasnega zračnega toka v raztopino 10,9 g (0,05 molov) 5-ciano-5H-dibenz[b,f]azepina v 110 mi ocetne kisline in 110 ml acetanhidrida, ki jo držimo pri 5θ°. Po 3 urah je presnova končana; nato topilo pod vakuumom oddestiliramo pri temperaturi kopeli 50°, ostanekAnalogous to the mode of operation described in Example 4, sodium nitrite gas is produced in a flask of 55 g (0.8 mol) of sodium nitrite and guided by a slow air stream into a solution of 10.9 g (0.05 mol) of 5-cyano -5H-dibenz [b, f] azepine in 110 m acetic acid and 110 ml of acetanhydride, held at 5θ °. After 3 hours the metabolism is complete; the solvent is then distilled off under vacuum at a bath temperature of 50 °, the residue

- 13 prevzamemo v 50 ml izopropanola in izkristalizirani material odsesamo po večurnem stanju pri 20°. Dobimo 5-ciano-40-nitro5H-dibenz[b,f]azepin, ki je identičen s proizvodom, dobljenim po primeru 4.- 13 is taken up in 50 ml of isopropanol and the crystallized material is sucked off at 20 ° in the evening. 5-cyano-40-nitro5H-dibenz [b, f] azepine is obtained which is identical to the product obtained in Example 4.

Dobitek: 9,5 g, 72,5 % teor.Yield: 9.5 g, 72.5% of theory.

PBIMER 6PBIMER 6

Analogno načinu dela, opisanem v primeru 4, proizvedemo v buči iz 3θ»θ g (0,43 molov) natrijevega nitrita nitrozne pline in jih vodimo s pomočjo počasnega zračnega toka v raztopino 40,9 g (0,05 molov) 5-ciano-5H-dibenz[b,f]azepina v 440 ml acetanhidrida, ki jo držimo pri 55°. Po končani presnovi (kontrola s tenkoslojno kromatografijo) reakcijsko zmes uparimo pod vakuumom pri temperaturi kopeli 50° in ostanek prevzamemo z 20 ml ocetne kisline. Pustimo šteti 2 uri pri 20°, kristalizat odsesamo in ga izperemo z malo ocetne kisline. Dobimo 5-ciano-40-uitro-5H-dibenz[b,f j azepin, ki je identičen s proizvodom, dobljenim po primeru 4.Analogous to the mode of operation described in Example 4, sodium nitrite nitrous gas is produced in a flask of 3θ »θ g (0.43 mol) and is led by a slow air stream to a solution of 40.9 g (0.05 mol) of 5-cyano -5H-dibenz [b, f] azepine in 440 ml of acetanhydride held at 55 °. After complete digestion (control by thin layer chromatography), the reaction mixture was evaporated under vacuum at a bath temperature of 50 ° and the residue was taken up with 20 ml of acetic acid. Leave to count for 2 hours at 20 °, suction off and wash off with a little acetic acid. 5-cyano-40-uitro-5H-dibenz [b, f] is azepine, which is identical to the product obtained in Example 4.

Dobitek: 9»4 g, 69,4 % teor.Yield: 9 »4 g, 69.4% of theory.

PBIMER 7PBIMER 7

40,0 g (0,046 molov) 5-ciano-5H-dibenz[b,f3azepina raztopimo v 400 ml toluola pri 55°. Iz tlačne steklenice počasi uvedemo v raztopino ob mešanju 5,0 g (0,054 molov) ^2θ4’ temperatura naraste do 60°, nato držimo reakcijsko zmes pri tej temperaturi, dokler ves izhodni material ni presnovljen (kontrola s tenkoslojno kromatogra14 fijo), potem ohladimo na 20° in toluolno fazo posušimo nad natrijevim sulfatom. Po uparjenju v vakuumu dobimo rdeče olje, ki ga prevzamemo v 5θ ml izopropanola. Po večurnem stanju pri 20° kristale odsesamo in izperemo z malo izopropanola. Dobljeni 5-ciano-10-nitro-5H-dibenz[b,f]azepin je identičen s proizvodom, dobljenim po primeru 1.40.0 g (0.046 mol) of 5-cyano-5H-dibenz [b, f3azepine was dissolved in 400 ml of toluene at 55 °. From the pressure bottle, slowly bring in the solution with stirring 5.0 g (0.054 mol) ^ 2θ4 ', the temperature rises to 60 °, then the reaction mixture is held at this temperature until all the starting material is digested (control by thin layer chromatography), then cooled. to 20 ° and the toluene phase is dried over sodium sulfate. Evaporation in vacuo gave a red oil which was taken up in 5θ ml of isopropanol. After an evening condition at 20 °, the crystals were aspirated and washed with a little isopropanol. The 5-cyano-10-nitro-5H-dibenz [b, f] azepine obtained is identical to the product obtained in Example 1.

Dobitek: 6,7 g, 56 % teor.Yield: 6.7 g, 56% of theory.

PRIMER 8EXAMPLE 8

43,6 g (0,2 mola) 5-ciano-5H-dibenz[b,f]azepina raztopimo v 25θ ml ocetne kisline pri 55° in iz tlačne steklsmce v 2 1/2 ure v raztopino uvedemo ob mešanju ^0^, pri čemer z občasnim hlajenjem vzdržujemo temperaturo pri 55°· Konec reakcije spoznamo po zelenem obarvanju raztopine (prebitek K₂0^7 kot tudi s kontrolo s tenkoslojno kromatografijo Pustimo ohladiti, mešamo še več ur pri sobni temperaturi in nato izločeno oborino odfiltriramo\jo izperemo z malo ocetne kisline. Z uparjenjem filtrata in raztapljanjem z acetonitrilom dobimo drugi kristalizat 5-ciano-10-nitro-5Hdibenz[b,f]azepina, ki je identičen s proizvodom, dobljenim po primeru 1.43.6 g (0.2 mol) of 5-cyano-5H-dibenz [b, f] azepine were dissolved in 25θ ml of acetic acid at 55 ° and introduced into the solution with stirring for 2 1/2 hours with stirring. , maintaining the temperature at 55 ° C by occasional cooling. · The end of the reaction is recognized by the green coloration of the solution (excess K ₂ O ^ 7 as well as by control by thin layer chromatography. was washed with a little of acetic acid. Evaporation of the filtrate and dissolution with acetonitrile gave a second crystallisate of 5-cyano-10-nitro-5Hdibenz [b, f] azepine identical to the product obtained in Example 1.

Celoten dobitek: 19,5 g, 37 % teor.Overall yield: 19.5 g, 37% of theory.

PRIMER 9EXAMPLE 9

43,6 g (0,2 mola) 5-ciano-5H-dibenz[b,f]azepina raztopimo v 25° ml ocetne kisline pri 55°. K temu dokapavamo ml vode, dokler se ne začne pojavljati motnost,in nato iz tlačne steklenice počasi uvedemo I^O^, dokler se v tenkoslojnem kromatogramu ne da več dokazati izhodne snovi. Ohladimo na 5° in 2 uri mešamo pri tej temperaturi, nato kristalizat filtriramo in ga izperemo z 80 %-no ocetno kislino. Dobimo 5-ciano-10-nitro-5H-dibenz[b,f 3 azepin, ki je identičen s proizvodom, dobljenim po primeru 1.43.6 g (0.2 mol) of 5-cyano-5H-dibenz [b, f] azepine were dissolved in 25 ° ml of acetic acid at 55 °. To this, add ml of water until turbidity begins to appear and then slowly introduce I ^ O ^ from the pressure bottle until the starting material can no longer be proved in the thin layer chromatogram. The mixture was cooled to 5 [deg.] And stirred at this temperature for 2 hours, then the crystallizate was filtered off and washed with 80% acetic acid. 5-cyano-10-nitro-5H-dibenz [b, f 3 azepine is obtained which is identical to the product obtained according to example 1.

Dobitek: 42,1 g, 80 % teor.Yield: 42.1 g, 80% of theory.

PRIMER 10EXAMPLE 10

45,6 g (0,2 mola) 5-ciano-5H-dibenz[b,f3azepina raztopimo v 175 ml ocetne kisline pri 55°. V raztopino uvajamo pri tej temperaturi ^°4 ^ačne steklenice toliko časa, dokler vsa izhodna snov ni presnovljena (kontrola s tenkoslojno kromatografijo) in se proizvod obori L Kato ob občasnem hlajenju po deležih dodamo 16,4 g (0,2 mola) natrije vega acetata in vzdržujemo temperaturo pri 50 do 55°. Kato 5 ure mešamo pri sobni temperaturi, filtriramo in kristalizat nato izperemo z ocetno kislino in vodo. Dobimo 5-ciano1O-nitro-5H-dibenz[b,f3azepin, ki je identičen s proizvodom dobljenim po primeru 1.45.6 g (0.2 mol) of 5-cyano-5H-dibenz [b, f3azepine were dissolved in 175 ml of acetic acid at 55 °. Introduce into the solution at this temperature ^ 4 ^ hourly bottles until all the starting material is digested (control by thin layer chromatography) and the product is precipitated L Kato is added 16.4 g (0.2 mol) of sodium with occasional cooling. veg acetate and maintain the temperature at 50 to 55 °. The mixture was stirred at room temperature for 5 hours, filtered and the crystallizate was then washed with acetic acid and water. 5-cyano10-nitro-5H-dibenz [b, f3azepine is obtained which is identical to the product obtained in example 1.

Dobitek: 56,1 g, 68,6 % teor.Yield: 56.1 g, 68.6% of theory.

PRIMER 11EXAMPLE 11

21,8 g (0,1 mol) 5-ciano-5H-dibenz[b,f3azepina razto pimo v 110 ml acetanhidrida pri 55°. V. to raztopino uvajamo iz tlačne steklenice 10,0 g (0,1 mol) N^O^ tako počasi, da ne izhajajo temnorjavi plini, in temperaturo vzdržujemo z občasnim hlajenjem pri 55°. Po koncu reakcije 4 uro prevajamo močan tok dušika, nato ohladimo na -20° in 2 uri držimo pri tej temperaturi. Nato rumeni kristalizat odsesamo in ga izperemo z malo acetonitrila, nakar dobimo 5-ciano40-nitro-5H-dibenz[b,f]azepin, ki je identičen s proizvodom, dobljenim po primeru 4. iii trat uparimo pri vakuumu pri temperaturi kopeli 50° v rdeče olje. Prevzamemo z 40 ml acetonitrila, pustimo 2 uri stati pri 5° in drugi kristalizat odsesamo.21.8 g (0.1 mol) of 5-cyano-5H-dibenz [b, f3azepine were dissolved in 110 ml of acetanhydride at 55 °. V. This solution is introduced from a 10.0 g (0.1 mol) N ^ O ^ pressure bottle so slowly that no dark gas is generated and the temperature is maintained by cooling to 55 ° C from time to time. At the end of the reaction, a strong stream of nitrogen was transferred for 4 hours, then cooled to -20 ° and kept at this temperature for 2 hours. The yellow crystallizate is then sucked off and washed with a little acetonitrile to give 5-cyano40-nitro-5H-dibenz [b, f] azepine, which is identical to the product obtained from Example 4. Or evaporated under vacuum at a bath temperature of 50 °. into the red oil. Take up with 40 ml of acetonitrile, allow to stand at 5 ° for 2 hours, and suck off the second crystallisate.

Celoten dobitek: 49,5 g 74,4 % teor.Overall yield: 49.5 g 74.4% of theory.

PRIMER 42EXAMPLE 42

24,8 g (0,4 mol) 5-ciano-5H-dibenz[b,f]azepina raztopimo v 440 ml acetanhidrida pri 50°. V to raztopino počasi uvedemo ob mešanju iz tlačne steklenice 42,0 g (0,43 molov) ^Ν2θ4» S cmer držimo temperaturo s hlajenjem med 5θ in 55°.24.8 g (0.4 mol) of 5-cyano-5H-dibenz [b, f] azepine were dissolved in 440 ml of acetanhydride at 50 °. To this solution is slowly introduced with stirring from the pressure bottle 42.0 g (0.43 moles) of ^{Ν 2θ4} »S cmera keeping the temperature by cooling the 5θ and 55 °.

Pustimo še 4 uro reagirati, nato skozi raztopino vodimo močan tok dušika in počasi dodamo 60 ml vode, pri čemer s hlajenjem vzdržujemo temperaturo pri 5° do 55°· Nato ohladimo na 5°» pustimo kristalizirati 4 uro in odfiltriramo. -Dobimo 5-ciano4O-nitro-5H-dibenz[b,f]azepin, ki je identičen s proizvodom, dobljenim po primeru 4.Allow to react for another 4 hours, then run a strong stream of nitrogen through the solution and slowly add 60 ml of water, keeping the temperature at 5 ° to 55 ° by cooling. Then cool to 5 °, let crystallize for 4 hours and filter. -We obtain 5-cyano4O-nitro-5H-dibenz [b, f] azepine, which is identical to the product obtained in Example 4.

Pil trat uparimo pod vakuumom in po prevzemu ostanka v 40 ml 80-%-ne ocetne kisline dobimo drugi kristalizat. Celoten dobitek: 24,5 g» 84,7 % teor.The pile was evaporated under vacuum to give a second crystallisate after the residue was taken up in 40 ml of 80% acetic acid. Total Yield: 24.5 g »84.7% of theory.

PRIMER 15EXAMPLE 15

9-5,6 g (0,2 mola) 5-ciano-5H-dibenz[b,f3azepina raztopimo v 45O ml acetanhidrida. V to raztopino uvajamo ob mešanju in občasnem hlajenju iz tlačne steklenice 19,0 g (0,206 molov) počasi, da temperatura ne naraste nad 25°. Po koncu presnove se raztopina obarva zeleno in proizvod se obori v kristalih. Mešamo 1 uro ob hlajenju z ledom in prevajanju močnega toka dušika, nato odfiltriramo in izperemo z malo etilestra ocetne kisline. Dobimo 5-ciano10-nitro-5H-dibenz[b,f]azepin, ki je identičen s proizvodom, dobljenim po primeru 1. Iz filtrata dobimo po uparjenju v vakuumu in prevzemu z etilestrom ocetne kisline drugi kristalizat.9-5.6 g (0.2 mol) of 5-cyano-5H-dibenz [b, f3azepine are dissolved in 45O ml of acetanhydride. 19.0 g (0.206 mol) was slowly introduced into this solution with stirring and occasional cooling from a pressure bottle so that the temperature did not rise above 25 °. After the metabolism is completed, the solution turns green and the product precipitates in crystals. The mixture was stirred for 1 hour under ice-cooling and a strong stream of nitrogen was then filtered and washed with a little of ethyl acetic acid. 5-Cyano10-nitro-5H-dibenz [b, f] azepine is obtained, which is identical to the product obtained in example 1. The filtrate is obtained after evaporation in vacuo and the second crystallisate is taken up with ethyl acetate.

Celotni dobitek: 42,5 S» 80,4 %teor.Total Yield: 42.5 S »80.4% Theor.

PRIMER 14EXAMPLE 14

55>θ 6 (0,16 molov) 5-ciano-5H-dibenz[b,f 3 azepina suspendiramo v 160 ml acetanhidrida pri 20°. K temu pustimo ob mešanju 5 ur počasi dokapavati raztopino 14,7 g (0,16 molov) v 160 ml acetanhidrida, pri čemer držimo temperaturo med 20 in 25°. Po popolni presnovi izhodne snovi (kontrola s tenkoslojno kromatografijo) ohladimo z 1-urnim prevajanjem močnega toka dušika na 0 do 5° in kristalni proizvod odsesamo. Dobimo 5-oiano-10-nitro-5H-dibenz(b,f)azepin, ki je iden tičen s proizvodom, dobljenim po primeru 1.55> θ 6 (0.16 mol) of 5-cyano-5H-dibenz [b, f 3 azepine was suspended in 160 ml of acetanhydride at 20 °. To this, a solution of 14.7 g (0.16 mol) in 160 ml of acetanhydride was slowly added dropwise with stirring for 5 hours while maintaining the temperature between 20 and 25 °. After complete transformation of the starting material (control by thin layer chromatography), it is cooled by translating the strong stream of nitrogen to 0 to 5 ° for 1 hour and suctioning the crystalline product. 5-Oano-10-nitro-5H-dibenz (b, f) azepine is obtained which is identical to the product obtained according to Example 1.

Iz filtrata dobimo po uparjenju v vakuumu na 50 ml drugi kristalizat.The filtrate was obtained after evaporation in vacuo to 50 ml of the second crystallizate.

- 18 Celoten, dobitek: 54,6 g, 80 % teor.- 18 Overall, yield: 54.6 g, 80% of theory.

PRIMER 15EXAMPLE 15

45,6 g (0,2 mola) 5-ciano-5H-dibenz[b,f]azepina raztopimo v 175 ml anhidrida ocetne kisline pri 50°. Iz tlačne steklenice uvedemo v 2 urah v to raztopino toliko se izhodna snov popolnoma presnovi in v odpadnem plinu ugotovimo rahel prebitek H^O^. ^se proizvod izkristalizira pri 50® in nato po deležih dodamo 16,5 g (0,2 mola) natrijevega acetata. Eo se toplota neha razvijati, mešamo še 50 minut pri 50°, nato pa še več ur pri sobni temperaturi.45.6 g (0.2 mol) of 5-cyano-5H-dibenz [b, f] azepine were dissolved in 175 ml of acetic anhydride at 50 °. Introduce this solution from the pressure bottle within 2 hours until the starting material is completely metabolized and a slight excess of H 2 O 4 is found in the waste gas. ^the product was crystallized at 50® and then 16.5 g (0.2 mol) of sodium acetate was added in portions. Eo the heat stops developing, stirring for another 50 minutes at 50 °, and then for another hour at room temperature.

Po filtriranju in spiranju kri stali zat a z ocetno kislino in vodo dobimo 5-ciano-1O-nitro-5H-dibenz[b,f]azepin, ki je identičen s proizvodom, dobljenim po primeru 1. Z obdelavo matične lužnice lahko dobimo nadaljnje 5 g spojine.After filtering and washing the crystals with acetic acid and water, 5-cyano-10-nitro-5H-dibenz [b, f] azepine is identical, which is identical to the product obtained in Example 1. A further treatment of the mother liquor can give 5 g of the compound.

Celoten dobitek: 44,1 g, 85,8 % teor.Overall yield: 44.1 g, 85.8% of theory.

PRIMER 16EXAMPLE 16

K raztopini 2,0 g 5-ciano-5H-dibenz[b,f]azepina v 20 ml acetanhidrida ocetne kisline dokapavamo pri 20° ob mešanju 5 ml konc. solitrove kisline (okoli 64 %-ne), pri čemer poteče eksotermna reakcija ob spremembi barve do temnofrumene. Pustimo še 1 uro reagirati pri 20°, dokapamo nato pri 50° ml vode in prevzamemo oborjeno mast v etilestru ocetne kisline. Iz ostanka, ki ga dobimo po izpiranju in uparjenju organske faze, dobimo z acetonitrilom pri daljšem stanju 0,6 g rumenih kristalov, ki po kontroli s tekočinsko kro19 matografijo vsebujejo'78 % 5-ciano-lO-nitro-5H-dibenz[b,f]azepina.To a solution of 2.0 g of 5-cyano-5H-dibenz [b, f] azepine in 20 ml of acetic acid acetic anhydride was added dropwise at 20 ° with 5 ml conc. hydrochloric acid (about 64%), the exothermic reaction proceeds when the color changes to darkfruity. Allow to react at 20 ° for 1 hour, then drop at 50 ° ml of water and take up the precipitated fat in ethyl acetate. From the residue obtained after washing and evaporation of the organic phase, 0.6 g of yellow crystals containing '78% 5-cyano-10-nitro-5H-dibenz [b , f] azepine.

PRIMER 17EXAMPLE 17

Suspenziji 26,5 g (0,1 mola) 5-ciano-10-nitro-5H-dibenz[b,f]azepina v 100 ml ocetne kisline dodamo pri sobni temperaturi 50 ml raztopine 15 mas.% BP^ v ocetni kislini (= 0,11 molov). Pri tem temperatura naraste počasi na 54° ob popolnem raztapljanju izhodne snovi. Pri 5θ° 5 minut dodajamo 5θ ml vode, kar vodi do ponovnega porasta temperature na 57°. Pri tej temperaturi v 20 minutah po deležih vnesemo 40 g železovega prahu, pri čemer vzdržujemo temperaturo z občasnim hlajenjem na 65 do 7θ°. Po prenehanju eksotermne reakcije mešamo še 15 minut in nato odfiltriramo anorganski material, ki ga nato 5-krat izperemo z malo ocetne kisline. Celoten filtrat dokapamo ob dobrem mešanju v 1 1/2 1 vode, nastalo oborino odfiltriramo po 2-umem mešanju in z vodo izperemo do nevtralnega. Po sušenju pri 60° v vakuumu dobimo 5-karbamil-10-okso-10,11-dihidro-5H-dibenz[b,f]azepin, ki je na osnovi IR-spektra identičen z avtentičnim materialom. Dobitek: 25,0 g, 91,2% teor.To a suspension of 26.5 g (0.1 mol) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine in 100 ml of acetic acid was added at room temperature 50 ml of a solution of 15 wt% BP ^ in acetic acid ( = 0.11 moles). The temperature rises slowly to 54 ° with complete dissolution of the starting material. At 5θ ° for 5 minutes, 5θ ml of water is added, causing the temperature to rise to 57 ° again. At this temperature, 40 g of iron powder is introduced in portions within 20 minutes, maintaining the temperature with occasional cooling to 65 to 7θ °. After the exothermic reaction has ceased, it is stirred for a further 15 minutes and then the inorganic material is filtered off, which is then washed 5 times with a little acetic acid. The whole filtrate was added dropwise with good stirring into 1 1/2 l of water, the resulting precipitate was filtered off after 2 ml stirring and washed with water until neutral. After drying at 60 ° in vacuo, 5-carbamyl-10-oxo-10,11-dihydro-5H-dibenz [b, f] azepine is obtained, which is identical to the authentic material on the basis of the IR spectrum. Yield: 25.0 g, 91.2% of theory.

PRIMER 18EXAMPLE 18

K suspenziji 26,5 g (θ,1 mola ) ^5-ciano-10-nitro5H-dibenz[b,f]azepina v zmesi 260 ml klorbenzola in 15θ ml ocetne kisline hitro dodamo 5θ ml raztopine 15 mas.% BP^ v ocetni /.kislini in dobimo ob šibkem ugrevanju bistro rumeno raztopino. Reakcijsko zmes mešamo 10 minut in nato v enem deležu dodamo 40 g železovega prahu. Ob dobrem mešanju 5θ minut dokapavamo 100 ml vode, pri Čemer naraste temperatura na 65°.To a suspension of 26.5 g (θ, 1 mol) of ^ 5-cyano-10-nitro5H-dibenz [b, f] azepine in a mixture of 260 ml of chlorobenzene and 15θ ml of acetic acid was rapidly added 5θ ml of a solution of 15 wt% BP ^ in acetic acid and a clear yellow solution is obtained by weak heating. The reaction mixture was stirred for 10 minutes and then 40 g of iron powder was added in one portion. With good stirring for 5θ minutes, add 100 ml of water, raising the temperature to 65 °.

Z zunanjim segrevanjem držimo temperaturo 2 uri na 60 do 65°» anorganski del odfiltriramo in ga speremo še s klorbenzolom in ocetno kislino. Po odločenju klorbenzolne faze le-to izperemo z vodo, dokler se ne začne kristalizacija proizvoda. Uparimo v vakuumu in ostanek prevzamemo s 100 ml metanola. Po odsesanju in izpiranju z malo metanola dobimo 5-karbamil-10okso-10,11-dihidro-5H-dibenz[b,f Jazepin, ki je na osnovi IRspektra identičen z avtentičnim materialom.With external heating, the temperature is kept at 60-65 ° C for 2 hours. The inorganic part is filtered off and washed with chlorobenzene and acetic acid. After the chlorobenzene phase is decided, it is washed with water until crystallization of the product begins. Evaporate in vacuo and take up the residue with 100 ml of methanol. After suction and washing with a little methanol, 5-carbamyl-10oxo-10,11-dihydro-5H-dibenz [b, f Jazepin is obtained, which is identical to the authentic material on the basis of IR spectrum.

Dobitek: 21,4 g, 85 %' teor;Yield: 21.4 g, 85% 'theory;

PRIMER 19EXAMPLE 19

E suspenziji 26,5 g (0,1 mola) 5-ciano-10-nitro-5H-dibenz [b,fJazepina v 200 ml ocetne kisline pustimo hitro dotekati 50 ml raztopine 15 mas.% Bl·^ v ocetni kislini. Mešamo 45 minut do popolnega raztapljanja in do prenehanja zmerno eksotermne reakcije. Pri 5θ° nato dodamo 40 g železovega prahu in 50 minut počasi dokapavamo 100 ml vode, pri čemer temperatura naraste na 65°. 15 ur mešamo pri sobni temperaturi, ponovno segrejemo na 60°, neraztopljeno odfiltriramo in še 5-krat izperemo z ocetno kislino. Filtrat uparimo v vakuumu na volumen okoli 100 ml in po kapljicah dodamo 400 ml vode. Zmes mešamo še 2 uri, odfiltriramo in filtrsko pogačo izperemo z vodo do nevtralnega J*o pušenju pri 5θ° v vakuumu dobimo 25,8 g (94-,4 % teor.) surovega proizvoda, ki ga prekristaliziramo iz 200 ml ocetne kisline/vode (8:2). Dobimo čist 5-karbamil21 l0-okso-10,11-dihidro-5H-dibenz[b,f]azepin, ki je na osnovi IR-spektra identičen z avtmtičmminaterialom.To a suspension of 26.5 g (0.1 mol) of 5-cyano-10-nitro-5H-dibenz [b, f] .Jazepine in 200 ml of acetic acid was allowed to rapidly infuse 50 ml of a solution of 15 wt% Bl · ^ in acetic acid. Stir for 45 minutes until complete dissolution and until moderately exothermic reaction ceases. At 5θ ° 40 g of ferrous powder are then added and 50 ml of water are slowly added dropwise over 50 minutes, increasing the temperature to 65 °. The mixture was stirred at room temperature for 15 hours, reheated to 60 °, filtered undissolved and washed with acetic acid for another 5 times. The filtrate was evaporated in vacuo to a volume of about 100 ml and 400 ml of water was added dropwise. The mixture was stirred for a further 2 hours, filtered off and the filter cake washed with water to neutral J * about smoking at 5θ ° in vacuo to give 25.8 g (94-, 4% of theory) of the crude product, which was recrystallized from 200 ml of acetic acid / of water (8: 2). Pure 5-carbamyl2110-oxo-10,11-dihydro-5H-dibenz [b, f] azepine is obtained, which is identical to the auto-mineral material on the basis of the IR spectrum.

Dobitek: 19,7 g, 78 % teor.Yield: 19.7 g, 78% of theory.

PRIMER 20EXAMPLE 20

31,5 g (0,12 molov) 5-ciano-10-nitro-5H-dibenz[b,f] azepina suspendiramo v 540 ml klorbenzola in hitro dodamo 98 ml raztopine 10 mas.% BF^ v ocetni kislini. Ob segrevanju na 5°° nastopi raztapljanje, takoj nato pa se začne izločati BF^-adukt 5-karbamil-10-nitro-5H-dibenz[b,f lazepina. Pustimo 2 uri kristalizirati v ledeni kopeli, odsesamo in izperemo z bencinom. Suhi vmesni proizvod raztopimo v zmesi 200 ml ocetne kisline in 55 ml vode. 5θ minut po deležih dodajamo 5θ g železovega prahu in temperaturo držimo s hlajenjem pri okoli 60°. Mešamo še 1 uro pri 50°, filtriramo in izperemo z ocetno kislino. Filtrat uparimo v vakuumu in ostanek prevzamemo s 5°O ml ·vode. Izločeni proizvod odsesamo, z vodo izperemo do nevtralnega in v vakuumu posušimo pri 5θ°· Dobimo 5-karbamill0-okso-10,11-dihidro-5H-dibenz[b,f]azepin, ki je na osnovi IR-spektra identičen z avtentičnim materialom.31.5 g (0.12 mol) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine are suspended in 540 ml of chlorobenzene and 98 ml of a solution of 10 wt% BF2 in acetic acid are quickly added. Upon heating to 5 °°, dissolution occurs, and immediately thereafter the BF ^ -duct 5-carbamyl-10-nitro-5H-dibenz [b, f lazepine begins to be eliminated. Allow to crystallize in an ice bath for 2 hours, vacuum and rinse with gasoline. The dry intermediate is dissolved in a mixture of 200 ml of acetic acid and 55 ml of water. 5θ g of ferrous powder was added portionwise over 5 minutes and kept at 60 ° C by cooling. The mixture was stirred at 50 ° for 1 hour, filtered and washed with acetic acid. The filtrate was evaporated in vacuo and the residue was taken up in 5 ° O ml · water. The precipitated product is filtered off with suction, washed with water until neutral and dried in vacuo at 5θ °. 5-carbamyl-10-oxo-10,11-dihydro-5H-dibenz [b, f] azepine is identical, which is identical to the authentic IR spectrum. material.

Dobitek: 26,0 g, 86 % teor.Yield: 26.0 g, 86% of theory.

PRIMER 21EXAMPLE 21

26,5 g (θ,1 mol) 5-oiano-10-nitro-5S-dibenz[b,f]azepina suspendiramo v zmesi 150 ml ocetne kisline in 100 ml konc. solne kisline. Pri 50° dodajamo ob mešanju po deležih 50 minut 40 g železovega prahu in ob hlajenju držimo temperaturo pri 60°. Še 5θ minut mešamo pri 50 do 60°, neraztopljeno odfiltriramo in izperemo z ocetno kislino. Filtratu dodamo dvojni volumen vode in 3-krat ekstrahiramo s po 100 ml metilenklorida. Združene organske faze izperemo z vodo, posušimo nad natrijevim sulfatom in uparimo. Kristalni ostanek suspendiramo v 100 ml izopropanola in odsesamo. Dobimo 5-ciano-10okso-10,11-dihidro-5H-dibenz/b,f/azepin s tal. 154 do 156°C (iz etanola).26.5 g (θ, 1 mol) of 5-oano-10-nitro-5S-dibenz [b, f] azepine were suspended in a mixture of 150 ml of acetic acid and 100 ml of conc. hydrochloric acids. At 50 °, 40 g of iron powder are added with stirring for 50 minutes and kept at 60 ° C during cooling. The mixture was stirred at 50-60 ° C for another 5θ minutes, filtered undissolved and washed with acetic acid. A double volume of water was added to the filtrate and extracted 3 times with 100 ml of methylene chloride. The combined organic phases were washed with water, dried over sodium sulfate and evaporated. The crystalline residue was suspended in 100 ml of isopropanol and aspirated. 5-cyano-10-oxo-10,11-dihydro-5H-dibenz / b, f / azepine is obtained from m.p. 154 to 156 ° C (from ethanol).

Dobitek: 21,8 g, 93,2 % teor.Yield: 21.8 g, 93.2% of theory.

PRIMER 22EXAMPLE 22

K suspenziji 23,4 g (0,1 mola) 5-ciano-10-okso-10,11dihidro-5H-dibenz/b,f/azepina v 40 ml ocetne kisline dodamo 50 ml raztopine 15 mas.% BF^ v ocetni kislini in mešamo, dokler ne poneha šibko razvijanje toplote. Z dodajanjem 15 ml vode po kapljicah ob porastu temperature na 40 do 45° dobimo bistro temno modro raztopino. Držimo 15 minut na 40° in nato počasi dodamo nadaljnjih 135 ml vode. Dobljeno kristalno oborino več ur mešamo pri sobni temperturi, nato odsesamo in izperemo z vodo do nevtralnega. Po sušenju pri 50° v vakuumu dobimo 5karbamoil-10-okso-10,11-dihidro-5H-dibenz/b,f/azepin, ki je na osnovi IR-spektra identičen z avtentičnim materialom.To a suspension of 23.4 g (0.1 mol) of 5-cyano-10-oxo-10,11 dihydro-5H-dibenz / b, f / azepine in 40 ml of acetic acid was added 50 ml of a solution of 15 wt% BF ^ in acetic acid acid and stir until weak heat develops. Adding 15 ml of water dropwise, increasing the temperature to 40 to 45 °, gives a clear dark blue solution. Hold for 40 minutes at 40 ° and then slowly add a further 135 ml of water. The resulting crystalline precipitate was stirred at room temperature for several hours, then sucked off and washed with water until neutral. After drying at 50 ° in vacuo, 5carbamoyl-10-oxo-10,11-dihydro-5H-dibenz / b, f / azepine is obtained, which is identical to the authentic material on the basis of the IR spectrum.

Dobitek: 24,2 g, 96,0 % teor.Yield: 24.2 g, 96.0% of theory.

Claims (4)

PATENTNI ZAHTEVKIPATENT APPLICATIONS 1. Postopek za pripravo novega intermediata, uporabnega v postopku za pripravo okso spojine, s formulo označen s tem da 5-ciano-5H-dibenz/b,f/azepin s formulo nitriramo v nižji alkankarboksilni kislini ali halogennižjialkankarboksilni kislini ali v anhidridu nižje alkankarboksilne ali halogennižjialkankarb oksilne kisline z bodisi didušikovim trioksidom, v danem primeru v prisotnosti kisika, didušikovim tetroksidom ali solitrovo kislino.A process for the preparation of a new intermediate useful in the process for the preparation of an oxo compound of the formula wherein 5-cyano-5H-dibenz / b, f / azepine of the formula is nitrated in lower alkanecarboxylic acid or halogen lower alkanecarboxylic acid or in lower alkanecarbic anhydride or halogenoalkanecarb oxyl acid with either nitrous trioxide, optionally in the presence of oxygen, nitrous tetroxide or nitric acid. 2. Postopek po zahtevku 1, označen s tem, da kot topilo uporabimo ocetno kislino, acetanhidrid ali njuno zmes.2. A process according to claim 1, characterized in that acetic acid, acetanhydride or a mixture thereof is used as the solvent. 3. Postopek po zahtevku 1 ali 2, označen s tem, da uporabimo 3 do 30 vol. delov topila na masni del 5-ciano-5Hdibenz/b,f/azepina.Method according to claim 1 or 2, characterized in that 3 to 30 vol. of solvents by weight of 5-cyano-5Hdibenz / b, f / azepine. 4. Postopek po enem od zahtevkov 1 do 3, označen s tem, da nitriramo v temperaturnem območju od 0° do 120°C, prednostno od 40 do 80°C.Process according to one of Claims 1 to 3, characterized in that it is nitrated in the temperature range from 0 ° to 120 ° C, preferably from 40 to 80 ° C.