DE1670231C3 - Process for the preparation of substituted 1,3-diazacycloalkenene (2) - Google Patents

Description

- (NHL- - (CH ₂ L-NH-

(D

mostly not borrowed the primary amino group in the molecule it is possible to introduce further substituents into the molecule without prior Schulz of this group.

The invention relates to a process for the preparation of substituted 1,3-diazacycloalkenene (2) of the general formula

or

-NH- (CH ₂ L-

(m = 1 or 2),; i 2 or 3, X is a chlorine or bromine atom or a cyano group and R ₁ and R ₂ , which can be identical or different, are hydrogen, a lower alkyl or alkoxy group, a trifluoromethyl group or a Mean chlorine or bromine atom or a cyano group, characterized in that a compound of the general formula

(11)

in which Z, η and R and R _{2 have} the meanings given above or R and R _{2 can} optionally also mean a nitro group, catalytically reduced with conversion of the nitro group (s) to (r) amino group (s), the product obtained is diazotized and the diazonium salt thus obtained is heated with copper (I) chloride, bromide or cyanide, which may be prepared in situ, and the compound of general formula I formed is isolated in a manner known per se.

45

From the documents of the Belgian patent 23 305 it is already known to use 2-arylamino-l, 3-diazacycloalkenes- (2) by heating arylisothiuronium salts together with alkylenediamine without use a solvent at temperatures between 100 and 200 C, preferably 140 to 180 "C, to represent. This process produces relatively good yields and made the synthesis possible for the first time of 2 - [(2,6-disubstit.-phenyl) -amino] -l, 3-diazacyclopentene- (2), which are particularly valuable as remedies, especially the valuable antihypertensive agent 2 - [(2,6-Diehlorphcnyl) -amino] -l, 3-diazacyclopentcn- (2).

In this process, however, it is first necessary to start with the respective arylisothiuronium salt of an appropriately substituted aniline. The multiply substituted anilines are, however, for the most part only accessible in a roundabout way, since due to the presence of the sensitive

in the Z one of the groups

• 5

or

- (NH) ₁₁ , - - (CH ₂ L-NH-

-NH- (CH ₂ L-

(hi = 1 or 2), / ι = 2 or 3, X is a chlorine or bromine atom or a cyano group and R ₁ and R ₂ , which can be identical or different. Hydrogen, a lower alkyl or alkoxy group, a trifluoromethyl group or a chlorine or bromine atom or a cyano group, which is characterized in that a compound of the general formula

(CH ₂ ) ,,

(H)

in which Z, η and R ₁ and R _{2 have} the abovementioned meanings or R ₁ and R _{2 can} optionally also mean a nitro group, the product obtained is reduced catalytically with conversion of the nitro group (s) to (r) primary amino group (s) diazotized and the diazonium salt thus obtained is heated with copper chloride, bromide or cyanide which may be generated in situ, and the compound of general formula I formed is isolated in a manner known per se.

The reaction described is particularly good for introducing only one chlorine or bromine atom or a cyano group in the phenyl nucleus, d. H. it succeeds particularly smoothly if only one Nitro group in the compounds of the general formula against chlorine or bromine or the cyano group should be exchanged. In the case of multiple exchanges, on the other hand, the yields achieved go into in some cases considerably.

With the help of the reaction described, it is possible to produce mixtures that are difficult to produce by other means to represent substituted compounds of the general formula I in a simple manner and a new one to be added To direct the chlorine or bromine atom or the cyano group exactly into a desired position without Isomers that are difficult to separate are shown.

The exchange of nitro groups for chlorine Bromine atoms or cyano groups on the phenyl nucleus of via a nitrogen-containing bridge in the 2-position phenyl-substituted 1,3-diazacycloalkenene (2) was not yet known from the literature. It was therefore Quite surprising and unforeseeable that the process according to the invention runs smoothly and is good Returns yields, especially because of the presence of

secondary amino groups in the 1,3-diazacyclopentene (2) ring or in the nitrogen-containing bridge between phenyl and l, 3-diazacyclopentene (2) part during diazotization to a considerable extent with the formation of N-nitroso compounds had to be reckoned with.
The following examples illustrate the invention.

example 1
2- (2,4-dichlorophenyl) -amino-1,3-diazacyclopentene- (2)

a) Production of the starting material
2- (2-chloro-4-nitrophenyl) -amino-1,3-diazacyclopentene- (2)

200 g (1.0 mol) of 2-chloro-4-nitrophenylformamide are introduced into a solution of 135 g of sulfuryl chloride in 300 ml of thionyl chloride ^{at 10 ° C.} The reaction mixture is then heated for 12 hours at 60.degree. C. After the elimination of HCl and SO _{2 has been completed,} insolubles are filtered off with suction after prior addition of about 1.5 l of petroleum ether and the filtrate is concentrated in a water jet volume. Excess thionyl chloride is removed here. The residue is fractionated in a high vacuum. This gives 25.3 g (= 10.0% of theory) of colorless 2-chloro-4-nitro-phenyl-isocyanide dichloride with a boiling point: bp 0.02 = 106 to 108 C.

The isocyanide dichloride (0.1 mol) is dissolved in 80 ml of absolute benzene and a solution of 7.3 ml of ethylenediamine (110%) in 25 ml of absolute benzene is slowly added dropwise to this solution at 5 to 10 ° C. (ice cooling) The residue on the filter is then dissolved in dilute hydrochloric acid, the insolubles are filtered off and the light yellow filtrate is made alkaline with dilute sodium hydroxide solution. 2 - chloro -A- nitrophenyl) - amino -1,3 - diazacyclopcnten- (2), is suction filtered, washed with plenty of water and dried to give 9.5 g (== 39.5% of theory) mp... : 229 to 231 C.

b) Exchange of the nitro group for chlorine

7.25 g (0.03 mol) of the nitro compound obtained according to a) are hydrogenated under normal conditions over Raney-Nickei using methanol-glycol monomethyl ether as a solvent mixture for 5 hours. After uptake of 2.251 H ₂ (theoretical uptake: 2.241 at 22 ° C. and 734 Torr), the hydrogenation is stopped, the catalyst is suctioned off and the brown-colored filtrate is concentrated in vacuo. The residue is taken up in 1 η hydrochloric acid and the solution is extracted with After alkalizing with 5N sodium hydroxide solution (ice cooling), the separated impurities are suctioned off and extracted with chloroform and ethyl acetate. The combined chloroform and ethyl acetate extracts are dried over anhydrous calcium sulfate and acidic by adding ethereal hydrochloric acid until a congic acid reaction The dihydrochloride of 2 - (4-amino-2-chlorophenylamino) -1,3-diazacyclopentene- (2) precipitates in a yield of 2.3 g. After filtering off with suction, washing and drying, it has a melting point. from 273 to 276 ⁰ C

1.25 g 2- (4-Amino-2-chlorophenylamino 1,3-diazacyclopenten - (2) - dihydrochloride (0.0045 mol) are dissolved in 10 ml of 0.5 N hydrochloric acid under cooling with ice at 0 ⁰ C 0 35 g NaNO ₂ (0.0045 mol) are added The diazonium salt solution thus obtained is converted at the same temperature into a solution of 1.5 g copper sulfate, 0.5 g NaCl and 0.37 g Na ₂ SO ₃ in 1.5 ml H ₂ O and 2.5 ml of HCl are added dropwise. The mixture is heated in a boiling water bath for about 1 hour. After cooling, the reaction mixture is made alkaline with 5N NaOH. The crude base which separates out is further purified as follows: After suctioning off, pressing off and drying on clay, it is dissolved in ether, insoluble fractions are filtered off and the ethereal base solution is purified over charcoal. The clear and colorless filtrate is then acidified with ethereal hydrochloric acid. 2- (2,4-dichlorophenylamino) -l separates , 3-diazacyclopenten- (2) in pure form in a yield of 0.3 g (= 25% of theory). It shows a melting point from 211 to 213 ° C.

Example 2

2- (2-chloro-4-bromophenyl) -amino-1,3-diazacyclopentene- (2)

2.5 g (0.009 mol) of 2- (4-amino-2-chlorophenyl) -aminol, 3-diazacyclopenten- (2) -dihydrochloride, obtained according to Example 1 b), are dissolved in 20 ml of 48% HBr and taken under Ice cooling at 0 C with a solution of 0.7 g NaNO ₂ in 4 ml H ₂ O. The diazonium salt solution is added dropwise at the same temperature to a solution of 3.0 g of copper sulfate, 1.8 g of NaBr and 0.75 g of Na ₂ SO ₃ in 3 ml of H ₂ O + 5 ml of 48% HBr. The mixture is heated in a boiling water bath for about 1 hour. After cooling, the reaction mixture is made alkaline with Sn-NaOH. 2- (4-Bromo-2-chlorophenyl) -aminol, 3-diazacyclopenten- (2) separates out. It is dissolved in ether and converted into its hydrochloride by adding ethereal hydrochloric acid until the Congo acidic reaction occurs. Yield: 0.55 g, which corresponds to a yield of 22.3% of theory. Mp .: 201 to 202 C (from methanol, ether).

In an analogous manner, by using Cu ¹ CN instead of Cu ¹ Br, 2- (2-chloro-4-cyanophenylamino -1,3-diazacyclopentene - (2) can be obtained from 2 - (4 - amino-2-chloro-phenylaniino) ) - 1,3 - diazacyclopentene - (2) synthesize. Mp .: (hydrochloride) 247 to 251 C, yield: 21.7% of theory.

Claims (1)

Claim: Process for the preparation of substituted 1,3-diazacycloalkenene (2) of the general formula N _x (CH ₂ ) " in the Z one of the groups