NO132320B - - Google Patents

Description

The present invention relates to a method for the production of benzodiazepine derivatives with the general formula

where R means hydrogen or halogen. The method according to the invention is characterized by reacting a compound with the general formula

where R has the above meaning, and

X means chlorine, bromine or iodine,

with hexamethylenetetramine.

From J. Org. Chem. 21, 3788-3796 (1962) it is well known to cyclize 2-(2-halo-N-methyl-acetamido)-5-chloro-benzophenone in the presence of ammonia to form 7-chloro-1,3-dihydro -1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one with a yield of 73%.

Later, in DOS 2,016,084, an improved process was described in that ammonia was replaced with hexamethylenetetramine. According to the improved process, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one was obtained in a yield of 80 to 90% and with a higher purity . However, a direct comparison of the purity is not possible, since in J. Org. Chem. no melting point is indicated, however, in the last-mentioned method, the yield was raised from approx. 73% to 80 - 90%.

In addition, in DOS 2,016,084 the cyclization of 2-halogenacetamido-benzophenones to 5-phenyl-2H-1,4-benzodiazepine-2-ones using hexamethylenetetramine is generally indicated. However, a close examination of this first method of preparation has shown that it is only suitable for the production of benzodiazepine derivatives with a substituent in the 1-position. Benzodiazepines which are not substituted in the 1-position cannot be prepared in preparative yields according to the above-mentioned "method", which is contrary to the statement given in the above-mentioned DOS.

Furthermore, from example 4 in Dutch patent document no. 122,319 it can be seen that 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one with a melting point of 238-240 °C can be prepared from 2-(2-amino-5-bromobenzoyl)-pyridine, bromoacetyl bromide and ammonia with a yield of 12.3%. According to the present method, the same benzodiazepine derivative can be obtained with a yield of 86% and with a melting point of 249-251°C by treating 2-(2-halogenacetamido-5-bromobenzoyl)-pyridine with hexamethylenetetramine. Since 2-(2-amino-5-bromo-benzoyl)-pyridine can be haloacetylated to 2-(2-halogenacetamido-5-bromobenzoyl)pyridine with a yield of 84 - 94%, a total yield of 73 - 81.5 can be obtained %. Compared to the method according to the aforementioned Dutch patent, the desired end product is obtained with the present method with a 6-7 times greater yield.

According to a special embodiment of the method according to

invention, the reaction of a compound of formula II with hexamethylenetetramine is carried out under slightly acidic conditions

see and in the presence of an aqueous, hydroxyl group-containing solvent, whereby a remarkable yield is obtained.-

ning of the desired benzodiazepine-2-one derivative.

The term "halogen" includes the 4 halogens chlorine,

bromine, fluorine and iodine. When R-^ means halogen, it means

preferably chlorine or bromine, whereby bromine is particular

preferred. Preparation of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one is preferred.

The reaction of a compound of formula II with hexamethylene-

tetramine is conveniently carried out in the presence of an inert organic solvent. Of the many suitable inert organic solvents

agents that can be used according to the invention are the following: lower alkanols, such as methanol, ethanol and the like, ethers such as tetrahydrofuran and the like, dimethylsulfoxide, dimethylformamide and similar inert organic solvents. The solvent must be chosen so that the starting material is soluble in it, and so that the solvent does not intervene in the reaction. Tem-

temperature and pressure are not critical for a successful implementation of the method according to the invention. However, the reaction is preferably carried out at a temperature between approx. room theme

perature and approx. the reflux temperature of the reaction mixture.

Particularly preferred is the use of higher temperatures.

Particularly suitable is a temperature of approx. the reflux temperature of the reaction mixture.

For the conversion of a compound of formula II into a corresponding compound of formula I, the compound of formula II is used

preferably in the form of a salt with a common non-oxidizing acid, e.g. a non-oxidizing mineral acid, such as a

hydrohalic acid (hydrobromic acid, hydrochloric acid, hydroiodic acid) or a non-oxidizing organic acid, such as

a C1-C4-lower alkane carboxylic acid (acetic acid, propionic acid, butyric acid deriv.), toluenesulfonic acid etc.

As indicated above, according to a special aspect of the invention, the reaction of a compound of formula II with hexamethylenetetramine is carried out under slightly acidic conditions and in the presence of an aqueous, hydroxyl group-containing solvent. The weakly acidic reaction conditions can be obtained by carrying out the reaction in the presence of an organic acid, such as formic acid, acetic acid, pivalic acid, chloroacetic acid or trifluoroacetic acid, or preferably in the presence of a strong inorganic acid, preferably chlorohydrocyanic acid. The aqueous, hydroxyl group-containing solvent is preferably an aqueous alkanol, whereby an aqueous lower

alkanol, such as aqueous methanol, ethanol, n-propanol, n-butanol and amyl alcohol. A particularly preferred solvent is aqueous methanol or aqueous ethanol. The proportion of water present in the solvent is preferably chosen so that a homogeneous reaction mixture is obtained under reflux conditions. The reaction conveniently takes place at a higher temperature, preferably at the reflux temperature of the reaction mixture. If the reaction is carried out at the reflux temperature, the reaction time, depending on the solvent used, can range from approx. 2 and approx. 20 hours. If aqueous methanol or aqueous ethanol is used as solvent, the reaction preferably takes place over the course of 7 to 16 hours at reflux temperature.

The reaction can also be carried out so that part of the hexamethylenetetramine is used in the form of an acid addition salt. The hydrochloride is preferably used. Thus, one can e.g. for' implementation of the reaction apply per mol of a compound of formula II 1 to 1.5 mol of hexamethylenetetramine and 0.5 to 1.0 mol of hexamethylenetetramine hydrochloride, whereby the reaction mixture under these reaction conditions exhibits a pH value of approx. 4.5 - 6.0.

According to a further method aspect, the hexamethylenetetramine can also be formed in situ from formaldehyde and ammonia.

Thus, one can e.g. prepare a mixture consisting of

a compound of formula II and a hydroxyl group-containing solvent, whereby the calculated amount of formaldehyde and ammonia is added to the mixture, and then hydrochloric acid is added.

The desired benzodiazepine-2-one derivatives of formula I can be isolated by simple cooling of the reaction mixture in crystalline form and under high purity.

The starting materials of formula II can be prepared easily by reacting a correspondingly substituted 2-(2-aminobenzoyl)-pyridine with a suitable haloacetyl halide, such as chloroacetyl chloride or bromoacetyl bromide. The preferred compounds of formula II are those where X represents a chlorine atom. Examples of compounds with formula II are 2-(2-chloroacetamido-5-bromo-benzoyl)pyridine and the corresponding 2-bromo compound.

Benzodiazepin-2-one derivatives of formula I are known and have valuable sedative, musk lr fr; salmon is end and anticonvulsant properties. The preferred benzodiazepine-2-one derivative of formula I is 7-bromo-1,3-r[hydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one.

The following examples illustrate the method according to the invention. All temperatures are given in °C.

EXAMPLE 1

69.3 g of 2-(2-amino-5-bromoberizoyl)pyridine in 200 ml of toluene are reacted with 23.3 ml of bromoacetyl bromide. The thereby formed hydrobromine in that of 2-(2-bromoacetamido-5-bromobenzoyl)pyridine is separated from the solvent, and added without drying to 78 g of hexamethylenetetramine in 1.8 l of ethanol. The reaction mixture is heated under reflux for 10 hours. The solvent is then distilled off on a steam bath under reduced pressure. The residue obtained is triturated with 250 ml of water, which contains so much aqueous ammonia

that the pH is 7 - 8. The crystalline suspension is filtered, and the product is washed with water and dried. This gives you a dividend

j of 70-80% of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodia-L

zepin-2-one with m.p. 225 - 235° (decomposition). Crystallization in dimethylformamide/ethanol gives a product with m.p. 243 - 245°

(fission).

In a similar manner to that described above, the following compounds are prepared: 1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one, m.p. 230 - 231° (decomposition) of 2-(2-bromoacetoamido-benzoyl)-pyridine; 7-chloro-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one, m.p. 224 - 225° (decomposition) of 2-(2-bromoacetamido-5-chlorobenzoyl)-pyridine; 7-broir -1, 3-dihydro-5-( 2-pyridyl)- 2H-1, 4-benzodiazepine-2-one of 2-( 2-chloroacetaniido-5-bromobenzoyl)-pyridine or of 2-(2- iodoacetamido-5-bromobenzoyl) pyridine.

EXAMPLE 2

69.3 g of 2-(2-amino-5-bromobenzoyl)pyridine is dissolved as described in example 1 in 2(2-bromoacetane ido-5-bromoyl)pyridine hydrobromide. The hydrobromide is separated from the solvent and without

dry, it is added to 101.1 g of hekdan-stylentetramine in 1.8 1 of methanol. The reaction mixture is stirred for 6 hours under reflux

lop and the solvent are then distilled off on a steam bath under reduced pressure. The crystalline residue is suspended in 250 ml of water, filtered, washed and dried, thereby obtaining a yield of 85% of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine- 2-on, m.p. 225 - 235° (decomposition). Krystallisa-

tion in dimethylformamide/ethanol gives pure material with m.p. 243 - 245° (decomposition).

EXAMPLE 3

A mixture of 99.5 g of 2-(2-bromoacetamido-5-bromobenzoyl)pyridine

and 78 g of hexamethylenetetramine in 1.2 1 ethanol are heated for 10 hours under reflux. The solvent is then distilled off under reduced pressure in the steam bath. The residue is suspended with stirring in 500 ml of water, isolated by filtration and dried, thereby obtaining a yield of 60 - 80% of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4- benzodiazepine-2-one, m.p. 225 - 235° (decomposition). After crystallization in dimethylformamide/ethanol, the product melts

243 - 245° (decomposition).

EXAMPLE 4

A mixture of 99.5 g of 2-(2-bromoacetamido-5-bromobenzoyl)pyridine and 78 g of hexamethylenetetramine is heated in a mixture of methanol and water (70/30 v/v%) for 10 hours at reflux. The reaction mixture is cooled to crystallization and the product is isolated by filtration, washed and dried. The crude 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one (yield 60-80%) melts at 220 - 235° (decomposition). Crystallization in dimethylformamide/ethanol gives a product with m.p. 243 - 245° (decomposition).

EXAMPLE 5

A mixture of 10.0 g of 2-(2-chloroacetamido-5-bromobenzoyl)pyridine, 8.1 g of hexamethylenetetramine, 12.75 ml of 2-N aqueous hydrochloric acid, 55 ml of methanol and 5.2 ml of water is heated under reflux for 7 hours . The reaction mixture is cooled and stirred for 1 hour at 0°. The thereby precipitated crystals are filtered off and washed with 20 ml of aqueous methanol. After drying at 60° under reduced pressure, 7.5 g are obtained, i.e. 80% conversion, of crystalline 7-bromo-1,2-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one with synp. 249 - 251°. With thin-layer chromatography, the presence of a further end product in the mother liquor can be demonstrated.

EXAMPLE 6

A mixture of 10.0 g of 2-(5-bromo-2-chloroacetamidobenzoyl)-pyridine, 8.1 g of hexamethylenetetramine, 0.7 g of 98% formic acid, 55 ml of methanol and 18 ml of water was refluxed for 18 hours. The mixture was then cooled to 0°C, stirred at 0°C for 1 hour and filtered. The solid residue was washed with 20 mL of aqueous methanol (75%) and dried at 60°C/10~ mm Hg, whereby 7.45 g (82%) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one with m.p. 243 - 246°C.

EXAMPLE 7

To a heated mixture of 10.4 g of paraformaldehyde, 40 ml of methanolic ammonia (10% w/v) and 30 ml of aqueous methanol (75%) was added 10.0 g of 2-(5-bromo-2-chloroacetamidobenzoyl)- pyridine and 6.4 ml of 2-N aqueous hydrochloric acid. The mixture was boiled under

refluxed for 18 hours, cooled to 0°C, stirred at 0°C for 1 hour and then filtered. The solid residue obtained was washed with

2o ml of aqueous methanol (75%) and dried at 6o°C/lo~<3> mm Hg, where-

with 6.85 g (77%) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one with melting point 244°-247° was obtained.

EXAMPLE 8

A mixture of lo,o g 2-(5-bromo-2-chloroacetamidobenzoyl)-pyridine,

6.06 g of hexamethylenetetramine, 2.56 g of hexamethylenetetramine hydro-;

chloride, 55 ml of methanol and 18 ml of water were refluxed for 16 hours. The mixture was cooled to 0°C, stirred at 0°C for 1 thaw and filtered. The solid obtained was washed with 10 ml of aqueous methanol (75%) and dried at 60°C/100 mm Hg, whereby 7.69 g (86%) of 7-bromo-1,3-dihydro- 5-(2-pyridyl)-2H-.1,4-benzodiazepine-2-one with melting point 248 -25o°C.

EXAMPLE 9

A mixture of lo.o g (o.o28 mol) 2-(5-bromo-2-chloroacetamidobenzoyl)-pyridine, 4.91 g (o.o35 mol) hexamel!/lenetetramine, 3.72 g (o, o21 mol) of hexamethylenetetramine hydrochloride, 55 ml of methanol and 18 ml of water were heated under reflux for 13 hours. The mixture was cooled to 0°C, stirred at 0°C for 1 hour and filtered.

The solid obtained was washed with 6 ml. aqueous methanol

(75%) and dried at 6o°C/lo~3 mm Hg to give .7.69 g (86%) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1 ,4-benzodiezeoin-2-

9 o

on with a melting point of 249 -251 C.

EXAMPLE lo

A mixture of lo,o g (o,o28 mol) 2-(5-bromo-2-chloroacetamidobenzoyl)

-pyridine, 3.93 g (o.o28 mol) hexamethylenetetramine, 4.95 g (o.o28

mol) of hexamethylenetetramine hydrochloride, 55 ml of methanol and 18 ml

■water was heated under reflux for 7 hours. The mixture was there-

after processing as described in example 9, whereby 7.15 g (8o%) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one with melting point 249°-251°C.

Claims (1)

1. Process for the preparation of benzodiazepine derivatives with the general formula where R means hydrogen or halogen, characterized by reacting a compound with the general formula where R. has the above meaning, and where X means chlorine, bromine or iodine, with witch amethy1ent etrami n„ 2„ Process according to claim 1, characterized in that the reaction of a compound of formula II with hexamethylenetetramine is carried out under slightly acidic reaction conditions and in the presence of an aqueous, hydroxyl group-containing solvent.