DE2640599A1 - Prepn. of 1,4-benzodiazepine cpds. - by reacting e.g. a 2-haloethyl-amino-benzophenone with hexa: methylene tetr:amine in presence of an ammonium salt and water alcohol solvent - Google Patents

Abstract

Prepn. of 1,4-benzodiazepines (I) comprises reacting a 2-(2-haloacylamino)- or 2-(2-haloethylamino)-benzophenone (IIe with hexamethylene tetraamine (HMTA) in a solvent mixt. contg. 5-50 (pref. 15-35) vol. % water and a water-miscible alcohol, in the presence of an ammonium salt of an acid of pKa 3.2 or less. (I) is obtd. in higher yields (more than 85%) cf. previous processes (50%) in a shorter reaction time (1/5-1/2 the time previously). Prodn. of by-prods. is lower and isolation of (I) is easier. The process is esp. suitable for the prodn. of e.g. 7-chloro-1-(2,2,2-trifluoroethyl)-5-phenyl-1,3-dihydro-2H-1,4-ben- zodiazepin-2-one and 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one- . Pref. ammonium salts are NH4Br, NHEI and NH4NO3.

Description

Process for the production of

The invention relates to a new improved method of manufacture of 1,3-dihydro-2H-1,4-benzodiazepin-2-ones and 2,3-dihydro-1H-1,4-benzodiazepines by condensation of 2- (2-haloacylamino) -benzophenone or 2- (2-haloethylamino) -benzophenone with hexamethylenetetramine in the presence of a solvent in the form of one with water miscible alcohol.

The use of dexamethylenetetramine in general manufacture of alkylamines and arylamines from the corresponding halides is general known (see e.g. ilouben-deyl, Methods of Organic Cnelllie, 4th ed., volume 11/1, nitrogen compounds II, pp. 105-107).

further publications (e.g. J. det. Chem. 7 (1970) 1173-1174, J. Het. Chem. 9 (1972) 531-537 and Dutch patent application 70-01765) the cyclization of 2- (2-haloacetamido) -benzophenones or 2 - (2-haloethylaiuno) -benzophenones with hexamethylenetetramine to form 1,3-dihydro-2H-1,4-benzodiazepin-2-ones and 1,2-dihydro-3H-1,4-benzodiazepines, respectively.

The process for the preparation of the 1,3-dihydro-2H-1,4-benzodiazepin-2-ones and 1,2-dihydro-3H-1,4-benzodiazepines can be in a stage or in two stages can be carried out. In the one-step process, the benzophenone and hexamethylenetetramine in an alcoholic solvent, e.g., absolute Ethanol or heated in ethanol containing no more than 15% water. With the two-stage The benzophenone and hexamethylenetetramine are allowed to move, for example in chloroform on the reflux condenser and optionally in the presence of potassium iodide or in acetonitrile react at room temperature, isolates among other things the intermediate product formed in the process, the is a complex of benzophenone and hexamethylenetetramine, and cyclizes this Intermediate in an alcoholic solvent, e.g.

Ethanol saturated with hydrochloric acid.

The invention is aimed at improving the one-step process directed and concerns the production of 1,4-benzodiazepines according to ne experience, uas is characterized in that 2- (2-haloacylamino) - or 2- (2-haloethylamino) benzophenones with hexamethylenetetramine in a mixture containing 5 to 50% by volume of water water-miscible alcohol with water in the presence of an ammonium salt of a acid which has a pKa value of 3.2 or less.

The new process is particularly suitable for producing 1,4-benzodiazepines of the formula from 2- (2-haloacylamino) -benzophenones or 2- (2-haloalkylamino) -benzophenones of the formula In these formulas, C stands for 0 or H2, R1 stands for a hydrogen atom or a lower alkyl radical or a lower fluoroalkyl radical, R2 and R³, which can be identical or different, stand for hydrogen atoms or lower alkyl radicals and X and Y, which can be identical or different , for hydrogen or halogen atoms or trifluoromethyl radicals, nitro groups ,, lower alkyl radicals, hydroxyl groups or lower alkoxy radicals.

By "lower alkyl", "lower fluoroalkyl" and "lower Alkoxy radicals "are alkyl radicals, fluoroalkyl radicals and alkoxy radicals from 1 to 6, in particular to mean from 1 to 4 carbon atoms.

As group X weu especially an itrogrupe or a halogen atom, e.g. a chlorine atom or a bromine atom are preferred.

This group is preferably in the 7-position of the benzodiazepine obtained. The group Y is preferably a hydrogen or halogen atom, for example a chlorine atom or fluorine atom. If Y is not a hydrogen atom, this group becomes the o-Stelluny particularly preferred.

The radical R1 is particularly advantageously a hydrogen atom, a methyl radical or fluoroethyl radical, e.g. a ß, ß-trifluoroethyl radical. L) as "halogen" in the formula II is preferably chlorine, bromine or iodine, especially bromine.

The new improved method has, compared to the known method, in which ilexamethylenetetramine is used without an ammonium salt, a number of Advantages, in particular increased yields, a lower level of by-products, easier isolation of the desired product and / or a reduced reaction time. For example, the known process for lierstelluny of 7-chloro-1- (2,2,2-trifluoroethyl) -5-phenyl-1,3-dihydro-2AI-1,4-benzodiazepin-2-one is applied, a low yield (about 50%) is obtained and the product is difficult to clean. in the new improved process, on the other hand, there is a yield of more than 85% achievable, and as shown by thin layer chromatography can be, the product obtained by the new process contains only a small amount Amount of byproducts. In addition, the new procedure requires a maximum of half and often only about a fifth of the response time of that in the above publication described procedure.

Particularly suitable ammonium salts for the new process are Ammonium bromide, chloride, iodide, sulfate, nitrate, citrate and tartrate. The special preferred salts from this group are ammonium bromide, ammonium iodide and ammonium nitrate. The ammonium salt is preferably added to the reaction mixture, but can may also be formed in situ. The hexamethylenetetramine and / or the Salts are preferably used in excess in this reaction, the molar ratio from benzophenone to hexamethylenetetramine to salt is preferably about 1: 4: 4.

As water-miscible alcohols are suitable for the improved Process for example methanol, ethanol, n- and isopropanol and t-butanol. Preferred are the last three alcohols mentioned. Preferably the alcohol contains 15 up to 35% by volume of water. The reaction can conveniently be carried out at a temperature of room temperature to Reflux temperature, especially at the reflux temperature be performed.

The method according to the invention is particularly advantageous for Preparation of 1,4-benzodiazepines of the general formula I in which R1 is a methyl radical or 2,2,2-trifluoroethyl radical, e.g. 7-chloro-1- (2,2,2-trifluoroethyl) -5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 7-chloro-1- (2,2,2-trifluoroethyl) -5- (ofluorophenyl ) -1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-chloro-1- (2,2,2-trifluoroethyl) -5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine, 7-chloro-2,3-dihydro-1-imethyl-5- phenyl-1H-1,4-benzodiazepine, 7-chloro-2,3-dihydro-2,3-dihydro-1- (2,2,2-trifluoroethyl) -5- (o-fluorophenyl) -1H-1 , 4-benzodiazepine and 7-chloro-5- (o-fluorophenyl) -1-methyl-2,3-dihydro-1Xi-1,4-benzodiazepine from a 2- [2-halogen-W- (2,2, 2-trifluoroethyl) acetamido] -5-chlorobenzophenone, a 2- [2-halo-N-methylacetamido) -5-chlorobenzophenone, a 2- [2-halo-N- (2,2,2-trifluoroethyl) acetamido] -5-chloro-2'-fluorobenzophenone, a 2- [2-halo-N- (2,2,2-trifluoroethyl) ethylamino] -5-chlorobenzophenone, a 2- (2-halo-N-methyl-ethylamino) -5-chlorobenzophenone, a 2-t-halo-N- (2,2,2-trifluoroethyl) ethylamino] -5-chloro-2'-fluorobenzophenone or a 2- (2-halo-N-methyl-ethylamino) -5-chlorobenzophenone. In these benzophenones the 2-halogen atom is most conveniently a 2-bromine atom.

The invention is further illustrated by the following examples: Example 1 7-chloro-1- (2,2,2-trifluoroethyl) -5phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one 21.7 g (0.05 mol) of 2-L2-bromo-N- (2,2,2-tri fluoroethyl) acetamido7-5-chlorobenzophenone are heated 28 grams (0.2 moles) of hexamethyldiazepine and 19.6 grams (0.20 moles) of ammonium bromide in 135 ml of an isopropanol-water mixture (volume ratio 85:15) for 2 hours on Reflux condenser. The reaction mixture is poured into water and extracted with benzene.

The benzene solution is washed with water and dried over anhydrous Sodium sulfate, filtered and evaporated to dryness. After recrystallization is pure 7-chloro-1,3-dihydro-1- (2,2,2-trifluoroethyl) -5-phenyl-2H-1,4-benzodiazepin-one obtain. The product shows a single spot on the thin layer chromatogram (Silica gel GF plates with ether-hexane = 1: 1. It has a melting point of 163.5 up to 1650C (corr.) and shows after mixing with an analytically pure authentic Sample no lowering of the melting point.

Practically the same result can be obtained if, for example 85% (V / V) aqueous n-propanol, 95% (V / V) or 65% (V / V) aqueous Isopropanol or 80% (V / V) aqueous t-butanol instead of 85% (V / V) Isopropyl alcohol is used in the experiment described above.

likewise, the same results can be obtained when in the experiment described above, for example 29.0 g of ammonium iodide (0.20 mol) or 16.0 g (0.20 moles) of ammonium nitrate can be used in place of ammonium bromide.

Example 2 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one 1.8 g (0.005 mol) of 2- (2-bromo-N-methylacetamido) -5-chlorobenzophenone, 2.8 are heated g (0.020 mole) hexamethylenetetramine and 1.96 g (0.020 mole) ammonium bromide together in 14 ml of 85% (V / V) aqueous isopropyl alcohol for 2 hours as a reflux condenser. Man Pour the reaction mixture into water and extract the product with benzene. Man wash the benzene solution with water, dry over anhydrous sodium sulfate, filter and evaporates to dryness. After recrystallization will be the desired Get compound in pure form. The thin layer chromatogram of this compound shows a single spot. After the product under reduced pressure at 1100C shows it mixed with an authentic sample no lowering of the melting point (129.5 to 130.5 ° C.) Example 3 7-chloro-1 3 3-dihydro-5-phenyl-2H-1, 4-benzodiazepin-2-one, 1.76 g (0.005 mol) are heated 2- (2-bromoacetamido) -5-chlorobenzophenone, 2.80 g (0.02 mol) hexamethylenetetramine and 1.96 g (0.020 mole) ammonium bromide in 14 ml of 85% (v / v) aqueous isopropyl alcohol 2 hours on the reflux condenser. The reaction mixture is poured into water and extracted with benzene The benzene solution is dried over anhydrous water-borne sulfate and filtered and evaporates to dryness. The desired compound is obtained after recrystallization in pure form. The thin layer chromatogram of the product shows a single one Stains (silica gel GF plates; benzene-ethyl acetate-acetic acid = 18: 3: 1); Melting point 213 to 215 ° C.

Practically the same result can be obtained if 14 ml of 85% (V / V) aqueous ethanol instead of 85% isopropanol for that described above Attempt is used.

Example 4 7-Chloro-1,3-dihydro-1- (2,2,2-trifluoroethyl) -5- (2'-fluorophenyl) -2H-1,4-benzodiazepin-2-one 1.13 g (0.025 mol) of 2- [2-bromo-N- (2,2,2-trifluoroethyl) acetamido] -5-chloro-2'-fluorobenzophenone are heated, 1.4 g (0.01 mol) of hexamethylenetetramine and) 98 g (0.01 mol) of ammonium bromide in pure form in 8 ml of an isopropanol-water mixture (volume ratio 85:15) for 4.75 hours to reflux condenser. The reaction mixture is poured into water and extracted with dichloromethane. You dry them Dichomethane solution over anhydrous sodium sulfate, filtered and evaporated. after recrystallization has the desired compound obtained a melting point of 123 to 1250C. Thin layer chromatography shows that the product is pure.

Example 5 7-Chloro-1- (2,2,2-trifluoroethyl) -5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-Man heated 0.05 mol of 2- [N- (2,2,2-trifluoroethyl) -2-bromoethylamino] -5-chlorobenzophenone, 0.20 mol of hexamethylenetetramine and 0.20 mol of ammonium bromide together in 135 ml of 85% strength (V / V) aqueous isopropyl alcohol for 2 hours on the reflux condenser. The reaction mixture is poured in water, extracted with benzene, the benzene solution washes with water, dries over anhydrous sodium sulfate, filtered and evaporated to dryness. After recrystallization the desired compound is obtained in pure form. On tiem thin layer chromatogram the product shows a single spot (silica gel GP plates with ether-hexane = 1: 1).

The melting point is 163.5-165 ° C (corr.) And shows after mixing no degradation with an analytically pure authentic sample.

Example 6 7-Chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine It is heated 0.005 mol of 2- (2-bromoethyl-methylamino) -5-chlorobenzophenone, 0.020 mol Hexamethylenetetramine and 0.020 pounds mol of ammonium bromide together in 14 ml of 85% (V / V) aqueous isopropyl alcohol reflux condenser for 2 hours. Pour the reaction r and extracts the product with benzene. ItK benzene solution with water, dries over anhydrous Sodium sulfate, filtered and evaporated to dryness. After recrystallization is obtain the desired compound in pure form. The thin layer chromatogram of the product shows a individual spots. vQ After drying under reduced pressure at 1100C shows the product after mixing with a authentic sample no lowering of the melting point (102-1030C).

Example 7 7-Chloro-2,3-dihyciro-1- (2,2,2-trifluoroethyl) -5- (2'-fluorophenyl) -1H-1,4-benzodiazepine 0.0025 mol of 2 - / - (2,2,2-trifluoroethyl) -2-bromoethylamino] -5-chloro-2'-fluorobenzophenone is heated, 0.01 mol of hexamethylenetetramine and 0.01 mol of ammonium bromide together in 8 ml of one Isopropanol-water mixture (volume ratio 85:15) for 4.75 hours on the reflux condenser. The reaction mixture is poured into water and extracted with dichloromethane. Man dry the dichloromethane solution over anhydrous sodium sulfate, filter and evaporates. After recrystallization, the desired compound is obtained in pure form Shape. Melting point 81-830C. Thin layer chromatography reveals that the product is pure.

The 1,4-benzodiazepines prepared by the process described above are well-known drugs.

Claims (16)

P a t e n t a n s p r ü c h e 1. Process for the production of 1,4-benzodiazepines, characterized in that 2- (2- £ Ialogenacylamino) or 2- (2-haloethylamino) benzophenones with hexaene methyltetramine in a mixture containing 5 to 50% by volume of water water-miscible alcohol with water in the presence of an ammonium salt of a Acid, which has a pXa value of 3.2 or less, is converted. 2. The method according to claim 1, characterized in that the Ammonium salt as such is added to the reaction mixture. 3. The method according to claim 1 and 2, characterized in that the benzophenone aass the formula and the 1,4-benzodiazepine obtained has the formula has, in which Q stands for 0 or H2, R1 stands for a hydrogen atom or a lower alkyl radical or a lower fluoroalkyl radical, R2 and R3, which can be identical or different, for hydrogen atoms or lower alkyl radicals and X and Y, which can be identical or different, represent hydrogen atoms or halogen atoms or trifluoromethyl radicals, nitro groups, lower alkyl radicals, hydroxyl groups or lower alkoxy radicals. 4. The method according to claim 1 to 3, characterized in that one as the ammonium salt ammonium bromide, ammonium chloride, ammonium iodide, ammonium sulfate, Ammonium nitrate, ammonium citrate or ammonium tartrate are used. 5. The method according to claim 1 to 4, characterized in that one used as the ammonium salt ammonium bromide. 6. The method according to claim 1 to 5, characterized in that one the alcohol used is methanol, ethanol, n-propanol, isopropanol or t-butanol. 7. The method according to claim 1 to 6, characterized in that one an alcohol-dasser mixture is used that contains 15 to 35% by volume of water. 8. The method according to claim 1 to 7, characterized in that one the reaction at a temperature ranging from room temperature to reflux temperature of the reaction mixture. 9. The method according to claim 8, characterized in that the reaction carried out at the reflux temperature of the reaction mixture. 10. The method according to claim 1 to 9, characterized in that one as the benzophenone, 2- [2-halo-N- (2,2,2-trifluoroethyl) -acetamdio] -5-chlorobenzopheneone unu uses 7-chloro-1- (2,2,2-trifluoroethyl) -5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one as the product receives. 11. The method according to claim 1 to 9, characterized in that one used as benzophenone 2 - (2 -Lfalogenn -ae ethylacetamido) -5-chlorobenzophenone and as the product 7-chloro-1,3-dihydro-1-ethyl-5-phenyl-211-1,4-benzodiazepin-2-one receives. 12. The method according to claim 1 bys 9, characterized in that one as benzophenone, 2- [halogen-N- (2,2,2-trifluoroethyl) acetamido] -5-chloro-2'-fluoro-benzophenone used and the product -Chlor-1,3-dyhydro-1- (2,2,2-trifluoroethyl) -5- (2-fluorophenyl) -2tj-1, 4-benzodiazepin-2-one is obtained. 13. The method according to claim 1 to 9, characterized in that one as the benzophenone, 2- [N- (2,2,2-trifluoroethyl) -2-haloyenethylamino7-5-chlorobenzophenone used and the product 7-chloro-1- (2,2,2-trifluoroethyl) -5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine receives. 14. The method according to claim 1 to 9, characterized in that one used as benzopnenone 2- (N-methyl-2-haloethylamino) -5-chlorobenzophenone and 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1tI-1,4-benzodiazepine is obtained as the product. 15. The method according to claim 1 to 9, characterized in that one as benzophenone, 2- [N- (2,2,2-trifluoroethyl) -2-haloethylamino] -5-chloro-2'-fluoro-benzophenone used and the product 7-chloro-2,3-dihydro-1- (212,2-trifluoroethyl) -5- (2l-fluorophenyl) -1H-1,4-benzodiazepine receives. 16. The method according to claim 10 to 15, characterized in that aaß the 2-halogen atom is a 2-bromine atom.