DE1670231A1 - New process for the preparation of 1,3-diazacycloalkenes substituted in the 2-position (2) - Google Patents

Description

D ,. F. Zusein-Dr. E. ^ p ^W Dr. R. Koenigjberg * -

Patent attorney M0nA.n 2, ΒΛ * - **

Case I / 883 (269a)
Dr.Ve/Rö

CH. BOEHRINGER SOHN, INGELHEIM AM RHEIN

New process for the production of 1,3-diaz & cycloalkenes substituted in the 2-position (2)

From the Belgian Patent 623 305 it is already known, 2-arylamino-l, 3-dlazacyc1oalkene (2) by heating Arylisothiuröniumsalzen together with AIkylend amines without the use of a solvent at temperatures between 100 - 200 ⁰ C, preferably 140 - l80 ° C to represent. This

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Process produces relatively good yields and made it possible for the first time to synthesize those particularly valuable as medicinal products 2- (2,6-disubstituted phenyl) -amino-1,3-diazacyclopentene (2), especially the valuable antihypertensive agent 2- (2,6-dichlorophenyl) -amino-1,3-diazaeyelopenten (2).

In this process, however, it is necessary to first select the respective arylisothiuronium salt starting from a corresponding to represent substituted aniline. The polysubstituted anilines are, however, only for the most part Detours accessible, as it is usually not possible due to the presence of the sensitive primary amino group in the molecule is to introduce further substituents into the molecule without prior protection of this group.

According to an older proposal in patent ... (patent application B 89 635 IVd / 12p, it is now possible to use the so-called isocyanide dichloride process for the first time also to present such 2-arylamino-l, 3-diazacycloalkenes in good yields, which on Phenyl nucleus are substituted with nitro groups. Such substances are only after the isothiuronium salt process very difficult to access, since anilines substituted with nitro groups hardly induce the formation of isothiuronium salts can be.

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The present invention now relates to a process for the production of in the 2-position via a nitrogen-containing Bridge phenyl-substituted I, j5-diazacycloalkenes (2) general formula

in which Z one of the divalent groups -J _n g or -NH- (CHg) _n , (m = 1 or 2), η one of the integers 2 or 3 * X a haloene atom or a cyano group and R ₁ and Ro, the are identical or different and are hydrogen, a lower alkyl or alkoxy group, a trifluoromethyl group or the substituents X defined above.

^It has been found that the compounds of the general formula I can be prepared in a simple manner by converting into compounds of the general formula

II

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in which Z and η has the meaning given above and PL and PL, which can be identical or different, are hydrogen, an alkyl, alkoxy, cyano or trifluoromethyl group, a halogen atom or optionally also a nitro group entering into the reaction denote the present nitro group (s) catalytically reduced to (r) primary amino group (s), the amino group (s) diazotized and the diazonium salt thus obtained is heated together with (optionally generated in situ) copper halide or cyanide. For the purpose of introducing a fluorine atom, the diazonium salt obtained according to the procedure described above can be used are also isolated and reacted with pluoboric acid to give the corresponding diazonium borofluoride the desired fluorine substitution takes place when it decomposes when heated.

The reaction according to the application is preferably to introduce only one halogen atom or one cyano group into suitable for the phenyl nucleus, i.e. it works particularly smoothly if there is only one nitro group in the compounds of the general formula II is to be exchanged for halogen or cyan. If there are multiple exchanges, they go obtained yields, on the other hand, have already decreased considerably in some cases.

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With the help of the reaction according to the application, it is possible to obtain mixed substituted products that are difficult to produce by other means To represent compounds of general formula I in a simple manner and a newly entering halogen atom or directing the cyano group exactly into a desired position without the formation of isomers which are difficult to separate.

The exchange of nitro groups for halogen or cyano on the phenyl nucleus via a nitrogen-containing bridge in 2-position phenyl-substituted I, j5-diazacycloalkenes (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 good yields supplies, especially because of the presence of secondary amino groups in the 1,3-diazacyclopentene (2) ring. or in the nitrogenous Bridge between the phenyl and 1,3-diazacyclopentene (2) part the formation of N-nitroso compounds can be expected to a considerable extent during diazotization had to.

The following examples illustrate the invention without restricting it;

example 1

2- (2,4-dichlorophenyl) -amlno-l _f 3-diazacyclopentene (2)

a) Preparation of the starting material 2- (2-chloro-4-nitrqphenyl) -amino-1,2-diazacyclopentene (2).

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200 g (1.0 mol) of 2-chloro-4-nitrophenylformamide are used

at 10 ° in a solution of 135 β sulfuryl chloride in / 6

300 ecm thionyl chloride entered. The reaction mixture is then heated at 60 ° for 12 hours. After the elimination of HCl and SOg has been completed, the insoluble matter is filtered off with suction after prior addition of approx. 1.5 liters of petroleum ether and the filtrate is concentrated in a water-jet vacuum. Excess thionyl chloride is removed here. The residue is fractionated in a high vacuum. This gives 25.5 S (= 10.0 % of theory) of colorless 2-chloro-4-nitro-phenyl-isocyanide dichloride (I) with a boiling point: ^bp 0.02 ^{= 106} " ¹⁰⁸ °.

The isocyanide dichloride I (0.1 mol) is dissolved in 80 ml of absolute benzene and a solution of 7.5 ml of ethylenediamine (110 %) in 25 ml of abs. Benzene slowly drips in (ice cooling). The mixture is allowed to rise to room temperature and the insolubles are filtered off with suction. The filter residue 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. The 1,> - diazacyclopentene (2) base which separates out, the 2- (2-chloro-4-nitro-phenyl) -amino-1,3-diazacyclopentene (2) (II). is suctioned off, washed with plenty of water and dried. Yield: 9.5 g (= 39 * 5 % of theory). M.p. 229-231 °.

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b) Exchange of the nitro group for chlorine

7 * 25 g (0.05 mol) of the nitro compound II obtained according to a) are under normal conditions using Raney nickel of methanol-glycol monomethyl ether as a solvent mixture hydrogenated for 5 hours. After recording 2.25 Liters of melting point (theoretical uptake: 2.24 liters at 22 ° C and 734 Torr), the hydrogenation is stopped, the catalyst is removed and the brown-colored filtrate is concentrated in vacuo. The residue is taken up in 1 η hydrochloric acid and the solution is purified after extraction with ether over activated charcoal. After this Alkalizing with 5 η sodium hydroxide solution (ice cooling) is suctioned off from deposited impurities and with chloroform and Rssigester extracted. The combined chloroform and ethyl acetate extracts are dried over Drierite and thoroughly Addition of essential hydrochloric acid until the Congo acid reaction is acidic. The dihydrochloride of 2- (4-amino-2-chlorophenylamino) -l, 3-diazaeyclopenten (2) (III) in a yield of 2.3 g. After vacuuming, washing and drying it shows a pp of 273 - 276 °.

1.25 g of 2- ^(4-ß mino-2-phenylamino-l, 3-diazacyclopenten (2) dihydrochloride (III) (0.0045 ^M ol) are dissolved in 10 ml of 0.5 hydrochloric acid and η ^ iskühlung 0.35 g of NaNO ₂ (0.0045 mol) are added at 0. The diazonium salt solution thus obtained is converted at the same temperature into a solution of 1.5 g of copper

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sulfate, 0.5 g NaCl and 0.37 g Na ₃ SO ₃ in 1.5 ml HgO and 2.5 ml HCl were added dropwise. It is heated in a boiling water bath for another hour. After cooling, the reaction mixture is made alkaline with 5 η NaOH. The crude base that separates out is further purified as follows: After suctioning off, pressing and drying on clay, it is dissolved in ether, insoluble parts are filtered off and the ethereal base solution is purified over charcoal. The clear and colorless piltrate is then acidified with ethereal hydrochloric acid, 2- (2,4-dichlorophenylamino) -i, 3-diazacyclopentene (2) separates in pure form in a yield of 0.3 g (= 25 % of the Theory) = ab. It shows a melting point of 211 - 213 ° and at the mixed melting point with material obtained by the isothiuronium salt process no depression. Thin-layer chromatography is also identical to 2- (2,4-dichlorophenylamino-1 , 3-diazacyclopentene (2). (TLC carried out on silica gel G according to Stahl; Schiittier's reagent was used for visualization.)

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Example 2

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

2.5 g (0.009 mol) 2- (4-amino-2-chlorophenyl) -amino-1,3-diazacyclopentene (2) -dihydrochloride (compound III of Example l) are dissolved in 20 ml of 48% HBr and under Ice cooling at 0 ° with a solution of 0.7 g of NaNO ₂ in 4 ml of HpO. The diazonium salt solution is added dropwise at the same temperature to a solution of 3.0 g copper sulfate, 1.8 g NaBr and 0.75 g Na ₃ SO ₃ in 3 ml H ₃ O + 5 ml 48 # HBr. It is heated in a boiling water bath for another hour. After cooling, the reaction mixture is made alkaline with 5 η NaOH. The crude base of 2- (4-bromo-2-chlorophenyl) -amino-1,3-diazacyclopentene (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 * that corresponds to a yield of 22.3 % of theory. Pp: 201-202 ⁽ (from methanol-ether).

In an analogous manner, by using Cu CN instead of Cu Br, the 2- (2-chloro-4-cyanophenylamino-l, 3-dlazacyclopentene (2) from 2- (4-amino-2-chlorophenylamino) -l, 3-diazacyclopenten (2) (compound III of example 1) synthesize Pp. (hydrochloride) 247-251 ⁰ C.

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Claims (1)

- ίο - Claim New process for the preparation of compounds of the general formula in Z one of the divalent groups - (NH) -, - (CH ₂ ) -NH or -NH- (CHp). (m = 1 or 2), η is one of the integers 2 or Jt ₃ X is a halogen atom or a cyano group and R and Rp, which are identical or different, are hydrogen, a lower alkyl or alkoxy group, a trifluoromethyl group or the above defined substituents X, characterized in that in compounds of the general formula / N -Ζ-ΐ (CHj "II in which Z and η has the meaning given above and R, as well as / 009884/2176 - li - R ₂ ,, which can be the same or different, denote hydrogen, an alkyl, alkoxy, cyano or trifluoromethyl group, a halogen atom or optionally also a nitro group entering the reaction, catalytically the present nitro group (s) to ( r) Amino group (s) reduced, the latter diazotized and the diazonium salt thus obtained either optionally heated with copper (I) halide or cyanide produced in situ or converted into the corresponding diazonium borofluoride by reaction with fluoroboric acid and the latter decomposed by heating. 009884/2176