DE1670483A1 - Process for the preparation of 1,4-benzodiazepine derivatives - Google Patents

Description

PATENTAN V / AL
D R. -I N G. V / O I.FF .. l \ 5 ARTi: LS, DR. BRANDES, D IL-ί M O. HcID 7 STUTTGART-N, LA. ^N -; 3E STRAGSE 51

Stuttgart, Nov. 14, 1967

DJ / rh / 8.2.67 Case I.

Res. No. 121 127

CRC Compagnia di Ricerche Chimiche SA , Chiasso

(Ticino, Switzerland)

Process for the preparation of 1,4-benzodiazepine derivatives.

The present invention relates to the preparation of derivatives of 1,4-benzodiazepine of the following Formula:

MR

wherein R represents a hydrogen atom or an alkyl radical, and X is a hydrogen atom, a halogen atom or a nitro

00988 ^ 2134

group means.

According to the invention, these compounds can be obtained by adding a compound of the formula:

II

in which X a hydrogen atom, a halogen atom or represents a nitro group and R, an alkyl or aryl radical means, reacts with a primary alkylamine.

Some compounds of the formula II are new compounds which have not yet been described in the literature became. Their preparation is described in the examples.

According to the previously known method of manufacture of l, 4-3enzqdiazepine is used as the starting product benzofenone or its derivatives used, converted into derivatives of the ^ -haloacetamide, which in turn in the presence converted into the quinazoline by dehydrating agents.

BATH

By ring expansion, the derivatives of ühinazoline obtained in this way become quaternary by means of organic bases Ammonium salts, ammonia or primary amines converted into derivatives of 1,4-benzodiazepine.

According to other known processes, derivatives of benzofenone are used in a similar manner or the Ring closure is carried out by means of ammonia, ethylenediamine or with the aid of OC-amino acids, and it can be also produce other derivatives of 1,4-benzodiazepine with the help of various operations, such as nitration, alkylation, oxidation, etc. The implementation However, all of these known methods take a long time due to the numerous steps required, one low yield is obtained and this makes the process uneconomical.

According to the method according to the invention, proportionally Pure products are obtained as the last stage in an autoclave with gaseous reactants is carried out.

The compounds of the formula II are obtained by reacting compounds of the formula III:

Cl

009887/2134

with various esters of aminoacetic acid. The ethyl aminoacetate (H ₂ NCH ₂ COOC ₂ H ₅ ) is best suited for this. The condensation takes place in the presence of a strong acid which is bound as salts (preferably hydrochloric acid salts) or bound to pyridine, for example pyridine hydrochloride.

The last stage, i.e. the replacement of the chlorine with simultaneous ammonolysis, takes place under pressure by means of primary aliphatic amines.

The compounds of formula I exhibit sedative effects when used therapeutically at various stress levels These conditions are administered and used as remedies applied in the form of tablets, capsules, syrup, etc.

For a better understanding of the present invention, some examples are given below for practical implementation of the claimed method, which in no way falls outside the scope of the present Restricts the patent.

Example 1;

20 g of 2,5-dichlorobenzofenone and 21 g of ethyl aminoacetate hydrochloride are placed in a flask equipped with a stirrer and reflux condenser filled, heated and continued heating for 5 hours. Afterward

009887/2134

the excess pyridine is distilled off under vacuum. An oily, viscous, dark residue is obtained, which in a high vacuum (less than o, l mm Hg) is distilled again to give the pure Schiff base is obtained with a boiling point of 185 ⁰ C at 0,2'mm Hg. This compound is used as an intermediate for the further synthesis of 1,4-benzodiazepine. For this synthesis it is not necessary to distill off the pyridine, but the entire contents of the flask are poured directly into the autoclave.
Example 2;

The obtained according to Example 1 reaction product is placed in an autoclave, admixed with 50 ml of dichloromethane and 100 g of methylamine, heated to 50 ⁰ G and held at this temperature for 6 hours, with the pressure to 15 atm. increases.

The temperature is also increased to 6O ⁰ C and kept at this level for 30 minutes. The contents of the autoclave are vigorously stirred during the entire warm-up period.

The contents of the autoclave are then cooled, placed in a flask and evaporated to dryness in vacuo. The dry residue is dissolved in a mixture of ether and petroleum ether (150 ml) with activated charcoal

Q09887 / 2134

mixed, heated and filtered. On cooling, the T-chloro-l-methyl-S-phenyl-SH-l ^ diazepin-2- (lH) -one crystallizes out, which are obtained and dried. The melting point is 125 - 126 ° C. Example 3?

The intermediate product obtained according to Example 1 is placed in an autoclave and mixed with 100 ml of bichloromethane and 100 g of ethylamine. The mixture is heated to 8O ⁰ C and 6 hours is maintained under vigorous stirring at this temperature. When the reaction has ended, the autoclave is cooled, the contents poured into a flask and evaporated to dryness under vacuum. The dry residue is dissolved in 2 × 100 ml of dichloromethane. The extract is evaporated to dryness and the residue is taken up in a mixture of ether and petroleum ether. The solution is concentrated to 15 ml and allowed to cool. The precipitated crystals are collected and dried to give the 7-chloro-l-ethyl-5-phenyl-3H-l, 4-benzodiazepin-2- (lH) -one .with a melting point of 129-130 ⁰ C is obtained.

009867/2134

Claims (3)

Patent claims: 1. Process for the preparation of derivatives of 1,4-benzodiazepine of the formula: wherein R is a hydrogen atom or an alkyl radical and
X denotes a hydrogen atom, a halogen atom or a nitro group, characterized in that a compound of the formula: N-CH ₂ COO-R ₁ wherein X is a hydrogen atom, a halogen atom or a 009887 ^ 2134 Mirogru:; pti and R, means an alkyl radical, with a :: ri: r.äroi: condensed aliphatic amine. 2. The method as claimed in claim 1, characterized in that XTiRn simultaneously carries out the set of halogen atoms in jt, eilun £ 2 and the ammonolysis of the ester group with reverse. 3. Process according to Claims 1 and 2, characterized in that the solvent used is a mixture of Pyridine and dichloromethane is used. 009887/2134