CH444872A - Process for the preparation of benzodiazepine derivatives - Google Patents

Description

  

  Process for the preparation of benzodiazepine derivatives The invention relates to a process for the preparation of benzodiazepine derivatives of the general formula
EMI0001.0010
         where R, chlorine or nitro, R2 ethylene or propylene and R3 hydrogen, methyl,

  or ethyl, and von SäuT.eadditionssahen these compounds. The preparation of 7-chloro-1,3-diil / hydro-1- (2'-hydroxy-ethyl) -5-phemyl-2H-1,4-benzodiazepin-2-one is particularly preferred. The process according to the invention consists in that a benz which is unsubstituted in the 1-position;

  odiazepine compound of the formula
EMI0001.0037
         or a 1-alkali derivative thereof, preferably after converting the 1-unsubstituted compound into the alkali compound, expediently the 1-sodium derivative,

      with a compound of the general formula X-R2-O R3, in which X is a removable group. This implementation,

   can in an inert solvent using one or more organic solvents such as methanol, ethanol, dimethylformamide, benzene, dimethyl sulfoxide, toluene or the like,

       dBe guided. The group denoted by X can be chlorine, bromine, iodine or any equivalent group such as mesyloxy, tosyloxy or the like; be.



  The temperature and the pressure are not important, and the reaction can be carried out both at room temperature and atmospheric pressure and at elevated temperatures and / or reduced pressures.

       Usual reagents for the formation of the 1-alkali derivative. are z. B. sodium ethoxide, sodium hydride and the like.



  The compounds of the formula I form acid addition salts with inorganic and organic acids, such as hydrohalic acids, eg. B.



       Hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, tartaric acid, chronic acid, camphor sulfonic acid, ethanesulfonic acid, ascorbic acid, salicylic acid, maleic acid and the like.



  The compounds of the formula I and their acid addition salts which can be used pharmaceutically have muscle-relaxing, sedative and anticonvulsant properties. You can internally, e.g.

   B. parenteral. Or enteral., Can be administered in usual phiarmaceutical usage forms. For example, they can be liquid or solid carriers, such as water, gelatin, starch, magnesium stearate, talc, vegetable oils or the like, to tablets,

          Capsules, solutions, emulsions can be processed using customary pharmaceutical methods.



  In the following examples, all temperatures are given in degrees Celsius.



  <I> Example 1 </I> 0 is added to a solution of 0.10 times 7-chloro-1,3-dihydro-5-phenyd-2H-1,4-benzodiazepin-2-one in 250 ml of anhydrous dimethylformamide , 11 times solid sodium methoxide too.

       To. The reaction mixture is heated for 15 minutes on a steam bath while stirring and is protected from atmospheric moisture, and a solution of 0.11 mol of 3-bromopropan-1-ol in 200 ml of anhydrous toluene is carefully added over the course of 30 minutes.

       Stirring is continued while heating on the steam bath for a further 11/2 hours and the resulting reaction mixture is then concentrated in vacuo at 50-60 '. The concentrated solution obtained is slowly poured into a mixture of ice and water (1: 1), a crude reaction product separating out.

   This is purified by chromatography in the form of a benzene solution on an aluminum oxide column. After evaporation of the eluates and recrystallization of the residue obtained from acetone / petroleum ether (boiling range 30-60), 7-Chl, 'or-1,3-dihyd'ro-1- (3'-hyd'roxy-propyl) - 5-phenyl-2H-1,

  4-'benzod'iazepin-2-one in the form of white cubic crystals with a melting point of 156-158. <I> Example 2 </I> To a solution of 0.10 mol of 7Chfor-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 250 ml of anhydrous dimethylformamide is added. 0.11 mol of solid sodium methoxide added.

       The reaction mixture is heated for 15 minutes on a steam bath while stirring and protected from atmospheric moisture, and a solution of 0 is then added over the course of about 30 minutes.

  11 Moll 2-bromoethanol in 200 ml of anhydrous toluene. The mixture is stirred and heated further on the steam bath for 11/2 hours and the resulting reaction mixture is then concentrated in vacuo at 50-60. The concentrated solution is slowly poured into a mixture of ice and water (1:

   1) poured, where crude reaction product is deposited. This is purified by chromatography in the form of a benzene solution on an aluminum oxide column. After evaporation of the eluates and condensation of the residue obtained from acetone, 7-chloro-1 is obtained,

  3-dihydro-1- (2 'hydroxy ethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one in the form of colorless prisms with a melting point of 159 to 160. <I> Example 3 </I> 0.10 mol of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one is dissolved in 250 ml of anhydrous dimethylformamide and then added with 0,

  11 moles of solid sodium methoxide. The reaction mixture obtained is heated for 15 minutes on the steam bath with stirring and under Schultz in front of atmospheric moisture. The heated reaction mixture is then added

  over the course of about 30 minutes carefully with a solution of 0.11 mol of 2-bromoethanol in 200 ml of anhydrous toluene. The stirring and heating are continued on the steam bath for a further 11/2 hours and then the RTI is reduced

   ID = "0002.0166"> obtained reaction mixture in a vacuum at 50-60. The concentrated solution is slowly m a mixture of ice and water (1:

   1) poured, whereby crystallized 1,3-Dihydlro-1- (2 'hydroxy-ethyl) -7-nitro-5-p'henyl-2H-1,4 benzodiazepin-2-one of melting point 231-233 ( Zerr.) Separates. By recrystallizing from ethanol. and finally, from acetone, colorless prisms with a melting point of 239-2401 (Zens) are obtained.



  <I> Example 4 </I> Adds 1,4-benzodiazepin-2-one to a solution of 0.10 times 7-Ch, lor-1,3-dihydro-5-phenyl-2H in 250 ml of anhydrous dimethylformamide 0.11 mol of solid sodium methoxide is added.

   The reaction mixture is stirred on a steam bath for 15 minutes under protection from atmospheric moisture and then carefully with a solution of 0, over the course of 30 minutes.

  11 mol of ss-bromoethyl-ethyl ether are added in 200 ml of anhydrous toluene. The stirring and heating are continued on the steam bath for a further 11/2 hours and the mixture obtained is then concentrated in vacuo at 50-60 degrees. The concentrated solution is in a mixture of ice and

      Water (1: 1) poured, where crude reaction product separates out. This is in the form of a benzene solution on a column of neutra! Texn aluminum oxide (degree of activity 11I)

          chromatographed. After evaporation of the eluate and recrystallization of the residue obtained from benzene / hexane (1:

  1) 7-chloro-1,3-dihydro-1- (2'-ethoxy-ethyl) -5-phenyl-2H 1,4-benzod'iazepin-2, one is obtained in the form of white cubic crystals with a melting point of 156 to 158.

      The monohydrochloride of this compound is obtained by dissolving the base in a small amount of methanol and adding methanolic 2N hydrochloric acid (1.2 equivalents) and diluting the solution with acetone.

    After recrystallization from methanol / acetone (with the addition of a small amount of methanolic hydrochloric acid before each recrystallization), the hydrochloride is obtained in the form of colorless prisms with a melting point of 212 to 214 (decomp.)

 

Claims (1)

PATENT CLAIM Process for the preparation of benzodiazepime derivatives of the general formula EMI0002.0304 wherein R, chlorine or nitro, R2 is ethylene or propylene and R3 is hydrogen, Means methyl or ethyl, denoted by the fact that one is a benzodiazepime derivative of the formula which is unsubstituted in 1-starring EMI0003.0010 or a 1-alkali derivative thereof, with a compound of the a (general formula X-R # -O-R3, wherein X converts a leaving group. SUBClaims 1. Method according to, patent claim, characterized by gekenh- that the reaction product obtained is converted into an acid addition salt with an acid. 2. The method according to claim, characterized in that the removable group X is chlorine, bromine or iodine. 3. The method according to claim, characterized in that 7-chloro-1,3-dihydro-5-phenyf-2H-1,4-benzodiaepin-2-one is first reacted with sodium methoxide and the resultant is 1-Sodium derivative then reacts with 2-Hydroxyäthyllbromid.