CH491939A

CH491939A - Process for the preparation of a compound of the benzodiazepine series

Info

Publication number: CH491939A
Application number: CH255070A
Authority: CH
Original assignee: Clin Byla Ets
Priority date: 1967-08-08
Filing date: 1968-08-05
Publication date: 1970-06-15

Description

ProcH# de pHparation d'un composd de la s#rie des benzodiaz#pines Method for the preparation of a compound of the benzodiaz#pine series

Dans son brevet fran#ais N,1 1455048. la titulaire a Ucrit, entre autres, des 5-(1-cyclohex#nyl)-2-oxo-2,3-di hydro-IH-benzodiaz#pines-(1,4) qui poss#dent des pro pri#tds pharmacologiques intdressantes, ainsi que la pre paration de ces benzodiaz#pines par d#shydrohalog#na tion des composds 5-(1-halog#nocyclohexyliqties) corres pondants. In its French patent N,1 1455048, the owner has described, inter alia, 5-(1-cyclohex#nyl)-2-oxo-2,3-di hydro-IH- benzodiaz#pines-(1,4) which have interesting pharmacological properties, as well as the preparation of these benzodiaz#pines by dehydrohalog#na tion of 5-( 1-halogenocyclohexyliqties) corresponding.

Or. la titulaire a trouv# qu'ä partir de la 7-nitro-5-(1 - chlorocyclohexyl) - 1 -m#thyl-2-oxo-2,3-dihvdro- 1 H-benzo diazdpine-(1,4), inconnue jusqu'ici, on pouvait, par Us hydrohalog#nation, obtenir une substance, dgalement in connue jusqu'ici, offrant des propridt#s particuli#rernent Interessantes au point de vue physiologique, en l'esp & c la 7-nitro-5-(1-cyclohex#nyl)-1-m#thyl-2-oxo-2,3-dihydro IH-benzodiaz#pine-(1,4) de formule: However, the holder has found that from de 7-nitro-5-(1 - chlorocyclohexyl) - 1 -m# ethyl-2-oxo-2,3-dihvdro- 1 H-benzo diazdpine-(1,4), unknown until now, it was possible, by Us hydrohalogenation, to obtain a substance, also known hitherto, offering particularly interesting properties from a physiological point of view, in particular 7-nitro-5-(1-cyclohex#nyl)-1-m#thyl-2- oxo-2,3-dihydro IH-benzodiaz#pine-(1,4) of formula:

Le tableau suivant donne les principales activit#s de ce produit : The following table gives the main activities of this product :

Dose efficace Concerne Epreuve 50 (),/o en nia,/kg voie orale Vie de relation Actographie spontan#e (souris) 22,5 d" Motricit# spontan#e (rat) env. 25 d-, Equilibration-Tige tournante (souris) ActivIt# iiiyorelaxante Traction (souris) 9 Activit# antiC0nVL11sivant,2 Anti-pentdtrazol (souris) 12 & Anti-#Jectrochoc (souris) env. 50 Activitd anxtolvtique Exploration (souris) env. 25 do Cornbativit# provoqu & (rat') < 10 Effective dose Concerns Test 50 (),/o in nie,/kg oral Life of relationship Spontaneous actography (mouse) 22.5 d" Spontaneous motor# (rat) approx. 25 d-, Balancing-Rotating rod (mouse) iiiyorelaxing ActivIt# Traction ( mouse) 9 AntiC0nVL11sivant activity,2 Anti-pentdtrazol (mouse) 12 & Anti-#Jectroshock (mouse) approx.50 Anxtolvtic activity Exploration (mouse) about 25 do Cornbativity # induced & (rat') < 10

Ces valeurs d#montrent une forte activitd sur Je syst#me nerveux central. These values show strong activity on the central nervous system.

La toxicit# algu# pour la sourts est faible (DL 1000 mg/kg i.p. entre 2500 et 3000 mg/kg p.o.) et, con- The algal toxicity for sourds is low (LD 1000 mg/kg i.p. between 2500 and 3000 mg/kg p.o.) and, con -

trairement ä toute attente, le nouveau compos# est moins toxique que le compos# correspondant dans Iequel un atome de chlore figure dans la position 7 ä la place du groupe nitro. Unsurprisingly, the new compound is ä less toxic than the corresponding compound in which a chlorine atom appears in position 7 ä in place of the nitro group.

On peut obtenir le compos# chlorocyclohexyliqtic servant de mati#re prerni#re en traitant la 7-nitro-5-cyclo hexyl- 1 -m#thyl-2-oxo-2,3-dihvdro-IH-benzodiaze'pine (1,4) par un Uriv# N-chlore ä'un amide d'acide car boxylique ou sulfonique. en particulier le chloro-succin imide. The chlorocyclohexyliqtic compound serving as a starting material can be obtained by treating 7-nitro-5-cyclohexyl- 1 -m#thyl-2-oxo -2,3-dihydro-1H-benzodiazepine (1,4) by an N-chlorine Uriv# to a carboxylic or sulfonic acid amide. especially chloro-succin imide.

L'exemple suivant, dans Iequel l'abreviation F" dd- signe le point de fusion pris au bloc de Kofler, illustre la pr#paration de la mati#re prerni#re ainsi que le pro c & i# selon l'invention, c'est-ä-dire la d#shydrohalog#na tion de la 7-nitro-5-(1-chlorocyclohexyl)-1-m#thyl-2-oxo 2,3-dihydro-IH-benzodiazdpine-(1,4) qui aboutit ä la 7- nitro-5-(1-cyclohexdnyl)-1-mdthyl-2-oxo-2,3-dihvdro-IH benzodiazdp)ne-(1,4),. The following example, in which the abbreviation F" dd- stands for the melting point taken from Kofler's block, illustrates the preparation of the raw material. #re as well as the pro c & i # according to the invention, that is to say the d#shydrohalog#na tion of 7-nitro-5-(1-chlorocyclohexyl)-1-m#thyl-2 -oxo 2,3-dihydro-1H-benzodiazdpine-(1,4) which results in ä the 7- nitro-5-(1-cyclohexdnyl)-1-mdthyl -2-oxo-2,3-dihvdro-1H benzodiazdp)ne-(1,4),.

Exernple a) Nitro-7 (chloro-1 cyclohexyl)-5 mdthyl-1 oxo-2 dihydro-2,3 IH-benzodiaz#pine-1,4. Example a) Nitro-7-(1-chlorocyclohexyl)-5-methyl-1-oxo-2,3-dihydro1H-benzodiaz#pine-1,4.

A une solution de 32g de nitro-7 cyclohexyl-5 me thyl-1 oxo-2 dihydro-2,3 IH-benzodiazepine-1,4 dans 450m1 de t6trachlorure de carbone, on ajoute 16g de N-chloro succinimide et on chauffe ä reflux pendant 1 heure 30. La rdaction, qui Umarre assez vivernent, doit 8tre moddr#e ä son Ubut. L'op#ration termin#e, on ajoute 250 ml d'eau au mdlange chaud et on agite vigou reusernent pendant 15 minutes. On laisse refroidir jus qu'ä cristallisation compl & e et on essore la suspension. On lave avec de Peau et un peu de t#trachlorure de car bone. On recristallise dans l'acdtate d'#thvie. On re cueille ainsi, en deux jets, 32.35 g d'un proäuit dont Je point de fusion F" <B≥ 190,1. Par Evaporation du t & ra chlorure r#siduaire, on recueille encore 0,9 g de produit ayant le Mime point de fusion. Le rendement total, cal cul# sur 33,15 g, est de 92,9 0,/o. A a solution of 32g of 7-nitro-5-cyclohexyl-1-methyl-2-oxo-2,3-dihydro-1,4-H-benzodiazepine in 450m1 of tetrachloride of carbon, 16g of N-chloro succinimide is added and ä refluxed for 1 hour 30. , which Umarre quite lively, must be modded ä its Ubut. When finished, add 250 ml of water to the hot mixture and stir vigorously for 15 minutes. The mixture is allowed to cool until complete crystallization and the suspension is drained. Wash with water and a little carbon tetrachloride. It is recrystallized in #thvie acetate. Thus, in two squirts, 32.35 g of a product is collected whose I melting point F" <B≥ 190.1. By Evaporation of the t & ra residual chloride, we still collect 0.9 g of product having the same melting point. The total yield, calculated on 33.15 g, is 92.9 0,/o.

b) Nitro-7 cyclohex#nyl-5 mdthyl-1 oxo-2 dlhvdro 2.3 IH-benzodiaz#pine-1,4. b) Nitro-7 cyclohex#nyl-5 mdthyl-1 oxo-2 dlhvdro 2.3 IH-benzodiaz#pine-1,4.

On chauffc ä lft, avec agitation, lOg du produit pr#par6 selon a) dans 100m1 de dirn#thyl formamide avec 10 g de carbonate de lithium. La rdaäion est com pl & te lorsque cesse le ddgagement de gaz carbonique. L'op8ration termin & . on refroidit, on filtre pour enie ver les sels min#raux et on #vapore le filtrat au bain marie sous vide ; on traite le rdsidu par de Nther et de Peau et on refroidit la suspension dans la glace. De la 1ft, is heated with stirring, 10g of the product prepared according to a) in 100m1 of dirn#thyl formamide with 10 g of lithium carbonate. The rdaäion is complete when the release of carbon dioxide ceases. The operation finished & . cool, filter to remove the mineral salts and evaporate the filtrate in a water bath under vacuum ; treat the residue with de Nther and of skin and the suspension is cooled in ice. Of the

solution #th#r#e. on recueille ainsi, en deux jets. 8,35 g que Pon recristallise dans Pac & ate d'#tliyie. On obtient des cristaux jaunes pesant 5,1 g - F, # 1591>. Par con centration de Facetate d'dthyle rdsiduaire, on recueille 1,5 g de produit ayant un point de fusion Fk = 157-,. Rendement : 74 %. #th#r#e solution. one collects thus, in two jets. 8.35 g that Pon recrystallizes in #tliyie's Pac & ate. Yellow crystals weighing 5.1 g - F, # 1591> are obtained. By concentration of residual ethyl facetate, 1.5 g of product having a melting point Fk = 157-,. Yield : 74%.

L'analyse #l#mentaire du compose intermediaire et du produit final a dt# en tr#s bonne concordance avec ]es valeurs th#oriques. Les spectres dans l'infrarouge et l'ultraviolet, ainsi que les spectres de rdsonance magn# tique nucMaire sont en accord avec la structure. The elemental analysis of the intermediate compound and the final product was in very good agreement with the theoretical values. The infrared and ultraviolet spectra, as well as the nuclear magnetic resonance spectra are in good agreement with the structure.

Claims

CLAIM

Procedure for the preparation of 7-nitro-5-(1-cyclohexd nyl)-1-m#thyl-2-oxo-2,3-dihydro-1 H-benzodiazdpine -(1,4) answering ä the formula :

caract#risd in that 7-nitro-5-(1-chloroc-# clohexyl) - 1 - mdthvl - 2 - oxo - 2,3 -dihvdro- 1 H-benzodiazepine-(1,4) ä dehydrohalogenation.

SUB-CLAIMS

1. Proc#U according to claim. characterized in that lithium carbonate is used as dehydrohalog#nation agent.

2. Proc # cid according to claim or sotis-claim dication 1, characterized in that qtt'on leads the dd "hydro halogdnation in dimdthyl formamide.