CH488712A - Process for the preparation of benzodiazepine derivatives - Google Patents

Description

  

      Process for the preparation of benzodiazepine derivatives The invention relates to a new process for the preparation of benzodiazepine derivatives, namely 1,4-benzodiazepin-2-ones of the general formula
EMI0001.0003
    where A is phenyl, monohalophenyl or pyridyl, R, and R_ are hydrogen, halogen, nitro, trifluoromethyl or alkyl up to 7 carbon atoms and R, hydrogen or alkyl up to 7 carbon atoms.



  The inventive method is characterized in that a compound of the formula
EMI0001.0013
    wherein A, R ,, R, and R, have the meaning given above Be, with a halogenating agent, the one
EMI0001.0017
   Has group in which X is halogen, to sets and the 3-halogen compound obtained is treated with ammonia.



  Compounds of the formula I can be used to prepare the corresponding compounds substituted in the 3-position by a hydroxyl group; here the amino group in the 3-position is converted into a hydroxy group.

    Preferred halogenating agents with a
EMI0001.0028
    Groups are those in which X is chlorine, bromine or iodine; Compounds of the formula are particularly suitable
EMI0001.0029
    in which formulas X is halogen, preferably chlorine, bromine or iodine and R "is hydrogen or alkyl up to 7 carbon atoms and the ring labeled I can be substituted or unsubstituted. If the ring is substituted, then lower alkyl is a substituent. tuent preferred.



  The formulas IIIa, IIlb and 1lIc include compounds such as N-chlorosuccinimide, N-bromosuccinimide, N-halo-lower alkanoylamide, e.g. N-chloroacetamide, N-chlorosulphonamide such as N-chlorobenzenesulphonamide, N-chloro-p-toluenesulphonamide and the like. like



  Any catalyst which forms free radicals and which brings about the halogenation of compounds of the formula II can be used in the process according to the invention. Ge suitable catalysts are azo-bis-lower alkyl nitriles such as azobisisobutyronitrile, di-lower alkyl peroxides such as di-tert. -Butyl peroxides, diacyl peroxides such as di-lower alkanoyl peroxides (e.g. acetyl peroxide),

          Peresters such as tert-butyl perbenzoate and tert-butyl perphthalate, hydroperoxides such as tert-butyl hydroperoxide, cumene hydroperoxide and the like. Azodiisobutyronitrile is preferred.



  In a preferred embodiment, the 1-talogenation is carried out in an inert organic solvent. Suitable inert organic solvents are aromatic hydrocarbons such as benzene, xylene, toluene and the like; chlorinated hydrocarbons such as chlorobenzene, carbon tetrachloride and the like. Temperature and pressure are not of long in this process step and it can therefore be worked at room temperature and atmospheric pressure or above room temperature.

   However, every person skilled in the art is familiar with the fact that the temperature at which the halogenation of compounds of the formula II is carried out is partly determined by the catalyst. It is known that some radical formations that are caused by cleavage of a bond take place at room temperature. The reaction can therefore be carried out at room temperature if a catalyst is used which dissociates at room temperature. Most catalysts which form free radicals only dissociate above room temperature. It is therefore preferred to carry out this step at suitable temperatures, preferably at the reflux temperature of the reaction medium.



  The second step of the process according to the invention comprises the conversion of the 3-H <<log-1,4-benzodi2tze- pine into corresponding compounds of formula 1.



  This can be done by treating a 3-halogen compound with ammonia in the presence of an inert organic solvent such as dichloromethane.



  The 3-amino compounds of the formula I obtained can, if desired, be converted into 3-hydroxy compounds by diazotization and subsequent heating with water.



  The expression all <yl up to 7 carbon atoms includes branched and unbranched hydrocarbon groups, such as meth, I, ethyl, n-propyl, isopropyl, isobutyl and the like. The expression (#Halogena includes all 4-halogens, i.e. iodine, Bromine, chlorine and fluorine, unless otherwise stated.

   The term eniederes .Acyl.) Denotes acyl radicals of aromatic carboxylic acids, such as benzoyl or a branched or unbranched lower alkanoyl radical, e.g. Acetyl, propionyl and the like. Suitable alkali and alkaline earth metals are sodium. Potassium, calcium, magnesium and dal.



       In compounds of the formula 1, A is preferably phenyl or 7-pyridyl, R is preferably hydrogen and R is preferably halogen, particularly preferably chlorine.



       In the following example, all temperatures are given in C. <I> Example </I> A solution of 5.4 g (0.02 mol) 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 3 g (0.022 mol) of N-chlorosuccinimide, 0.1 g of azodiisobutyronitrile and 200 ml of benzene are refluxed for 1 hour.

   The suspension obtained is evaporated to dryness and the residue, which contains 3,7-dichloro-1,3-dihydro-5-phenyl-2H-1,4- benzodiazepin-2-one, is suspended in 50 ml dichloromethane . The suspension obtained is added, with stirring, to 100 ml of dichloromethane which is saturated with ammonia. The mixture is stirred in an ice bath for 1 hour and at room temperature for 3 hours. The dichloromethane is removed in vacuo. The oily residue is taken up in 35 ml of acetonitrile and heated to reflux.

    After filtering, the acetonitrile filtrate is evaporated to dryness. Fractional recrystallization of the residue from ethanol gives red-brown 3-amino-7- - chloro-1,3 - dihydro-5-phenyl-2H-1,4 - benzodiazepin-2-one with a melting point of 187-192 (Zerr.) . After recrystallization from acetonitrile, pale brown crystals with a melting point of 218-22t) (decomp.) Are obtained.

 

Claims (1)

PATENT CLAIM I Process for the preparation of benzodiazepine derivatives of the formula EMI0002.0134 wherein A is phenyl, monohalophenyl or pyridyl, R; and R .. Hydrogen, halogen, trifluoromethyl, nitro or alkyl up to 7 carbon atoms and R .; Hydrogen or alkyl up to 7 carbon atoms, characterized in that one 'is a compound of the formula EMI0002.0146 with a halogenating agent which has an -N-X group in which X is halogen, and the 3-halogen compound obtained is treated with ammonia. SUBCLAIMS 1. Process according to patent claim 1, characterized in that a compound of the formula <B> 11 </B> is used, in which A is phenyl, R., hydrogen and R, halogen. 2. The method according to claim I, characterized in that a compound of formula II is used in which A is phenyl or a-pyridyl, R_ and R3 what is hydrogen and R, halogen. 3. Process according to claim 1 or one of the subclaims 1 and 2, characterized in that R, denotes chlorine. 4. The method according to claim I, characterized in that the halogenating agent has a -N -X group, wherein X means chlorine, bromine or iodine tet. 5. The method according to dependent claim 4, characterized in that the halogenating agent is a chlorinating agent. 6th Process according to claim or one of the dependent claims 4 and 5, characterized in that the halogenating agent used is a compound of the formula EMI0003.0018 EMI0003.0019 wherein X is as defined above, R "is hydrogen or an alkali metal and the ring I can be substituted or unsubstituted, and that the reaction is carried out in the presence of a radical-forming catalyst and an inert organic solvent. 7. Process according to dependent claim 6, characterized in that the catalyst is an azo-bis-lower alkylnitrile, di-lower alkyl peroxide, diacyl peroxide, a perester or hydroperoxide. PATENT CLAIM II Use of the compounds of the formula I obtained by the process according to claim I for the preparation of the corresponding compounds which are substituted in the 3-position by a hydroxyl group, characterized in that the amino group in the 3-position of these compounds of the formula 1 converts it into a hydroxyl group by diazotization and subsequent heating with water,