NO138141B - PROCEDURE FOR MAKING 2- (2-AMINOBENZOYL) PYRIDINES - Google Patents

Description

2-(2-aminobenzoyl)pyridines of the general formula

where R 1 bstyr hydrogen, iodine, bromine or chlorine and 1*2 hydrogen or lower alkyl, can be transferred to 1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2- on with the general formula

where R 1 and R 2 have the above meanings.

The latter compounds are known muscle relaxants and anticonvulsants.

The hitherto known methods for preparing compounds of formula I are known to give low yields. The method according to the invention enables the preparation of compounds of formula I with high yields and using the fewest possible reaction steps.

The method according to the invention is characterized by reacting a nitrile with the general formula

where and have the above meanings,

with one mole of phenyllithium, and then in a known manner with one mole of . 2-pyridyl metallic reagent, preferably 2-pyridyl lithium, after which the product obtained is hydrolysed.

Conveniently, the reaction is carried out in the presence of an inert organic solvent, such as an ether, e.g. diethyl ether, tetrahydrofuran and the like, a hydrocarbon such as benzene, toluene and the like. It is appropriate to carry out the reaction below. -10°C, special Mg suitable between -30 and -10°C. Particularly preferred is a temperature between -20 and -10°C. If the reaction mixture v is allowed to stand at the above temperatures, preferably with stirring, the corresponding compound of formula I is obtained after hydrolysis in good yields and using a minimum of reaction steps.

It appears that the nitrile with fcrmel III contains, in addition to the cyano group, an active hydrogen atom (namely on the amino and, respectively, the alkylamino group in the ortho position), which can also react with organometallic reagents (Zerewittinbff reaction). If the reaction with the 2-pyridyl metal reagent was carried out without prior treatment with 1 mol of phenyllithium, 2 mol of said 2-pyridyl metal reagent would be required to convert the nitriles of formula III into the 2-(2-aminobenzoyl)pyridines of formula I , but considering the price of the 2-pyridyl metal reagents, this would constitute a significant disadvantage.

However, the person skilled in the art could in no way expect that phenyllithium would selectively react with the aforementioned active hydrogen atom alone, but also presumably - at least partially - with the cyano group which would obviously result in the formation of a mixture of the desired product with formula I and the corresponding benzophenone derivative. However, it was very surprisingly discovered that this was not the case, and this was all the more surprising because when e.g. butyllithium was used instead of phenyllithium, a mixture of the desired compound of formula I and up to 20% of the corresponding butyl ketone was obtained - as one would also have had to wait when using phenyllithium.

Thus, the important intermediates of formula I which can be converted to pharmaceutically active compounds of formula II can be recovered by a simple preparative method.

The term "lower alkyl" used in this description denotes straight-chain and branched hydrocarbon groups with 1-7 carbon atoms, such as methyl, propyl, butyl, pantyl and the like.

The following examples illustrate the invention. All temperatures are given in degrees Celsius.

EXAMPLE 1 ]

A solution of 5.58 g (27.5 mmol) of 2-amino-5-bromobenzonitrile in 40 ml of abs. ether is stirred under argon, cooled to 0° and then 29 ml of a phenyllithium solution is added dropwise.

(30.4 mmol) over the course of 12 minutes, whereby a yellow solid precipitates out.

in

In a second reaction vessel, 30 ml of a converted phenyllithium-; solution (31.5 mmol) under argon to 0°, and a solution of 4.47 g (28.3 mmol) of 2-bromopyridine in 15 ml of abs. ether in lbpet of 8 minutes. After the addition is finished, it is still stirred for 5 minutes at 0°. After cooling to -10°, add the suspension of the above-mentioned yellow precipitate,! whereby momentarily a hardened solid falls out. It is then stirred for 2 hours at 0°, and then the reaction mixture is poured into 100 ml of ice-cold 3N hydrochloric acid. The aqueous phase is separated and the ether phase is extracted with 50 ml of 3N hydrochloric acid. The combined aqueous extracts are added slowly with stirring to 40 ml! of an ice-cold ammonium accoplosnihg. The precipitated yellow crystals are sucked off and dried in a vacuum at 50°. Recrystallization of the j crude product from isopropanol and washing the recrystallized product with a small amount of hexane gives 2-(2-amino-5-bromobenzoyl)pyridine, melting point 99-100°.

It used 2-amino-5-bromobenzonitrile as starting material

can be produced as follows:

A solution of 80 g (1.0 mol) of bromine in 100 ml of dry methylene chloride is added very quickly over the course of 3-5 minutes to a strongly stirred solution of 59 g (0.5 mol) of anthranilonitrile in a solution of 50 ml of glacial acetic acid and 700 ml dry methylene chloride.

As the reaction is exothermic, a boiling bath is used so that the temperature does not exceed 30°C. The reaction mixture is then allowed to stand for one hour at room temperature and then diluted with 500 ml of cold tap water. The resulting white reaction product dissolves again very quickly

The reaction mixture is neutralised, by careful addition of sufficient solid sodium bicarbonate at pH 5-6. The methylene chloride phase is separated and washed free of the inorganic salts. The washing water is carefully separated, and the organic solution is evaporated by distillation to a volume of 200 ml. The 2-amino-5-bromobenzonitrile obtained in this way crystallizes. by standing overnight at room temperature. The product is filtered off, washed with Skelly B and dried. overnight in vacuum at room temperature. The product melts at 95°.

EXAMPLE 2

A solution of 4.25 g (36 mmol) of anthranilonitrile in 20 ml of abs. ether is stirred under argon and 50 ml of a phenyllithium solution (36 mmol) is added dropwise at 20°, whereby a yellow

solid precipitates out.

In a second reaction vessel, 55 ml of a phenyllithium solution (39.6 mmol) is cooled under argon to 0<0>~ and an ice-cold solution of 3.69 g (36 mmol) is added dropwise over 8 minutes.

: 2-bromopyridine in 10 ml abs. ether. After the addition is complete, the motherwort reaction mixture is stirred for 5 minutes at 0°. It is then cooled to -10° and the suspension of it

the above-mentioned deduction is added. The mother red reaction-o

; mixture is stirred for 2 hours at 0°, and then it is worked up as described in example 3, whereby crude 2-(2-aminobenzoyDpyridine is obtained. Recrystallization of the crude product from methylene chloride gives a pure product with a melting point of 146 to

147°.

The anthranilonitrile used as starting material can be prepared as follows: ! 142 g (1 mol) phosphorus pentoxide is added to a hot solution of 136.2 g (1 mol) anthranilamide in 500 ml pyridine„ Reaction the mixture is heated for 3 1/2 hours to reflux temperature, cooled to room temperature and one liter of ice water and 500 ml of benzene are added. The two-phase system is stirred until all the phosphoric acid has dissolved. After buffering with 100 ml of a 28% aqueous ammonia solution, the benzene phase is separated and washed with water.

The aqueous phase is extracted twice with 100 ml of benzene. The

combined benzene extracts are dried over sodium sulfate and evaporated. Distillation of the residue over a short Vigreux column under reduced pressure gives the anthranilonitrile as a colorless liquid, boiling point 90-95°/0.5 mm Hg, which solidifies and melts at 77-49°.

Claims (1)

Process for the preparation of 2-(2-aminobenzoyl)-pyridines of the general formula where R1 means hydrogen, iodine, bromine or chlorine, and R2 hydrogen or lower alkyl, characterized in that a nitrile with the gene real formula where R, and R2 have the meanings given above, is first reacted with 1 mol of phenyllithium and then in a known manner with 1 mol of 2-pyridyl metallic reagent, preferably 2-pyridyl - lithium, after which the product obtained is hydrolysed.