DD200619A1 - PROCESS FOR PREPARING 1,2-DISUBSTITUTED DELTAQUADRATE IMIDAZOLINES AND THEIR SALTS - Google Patents

Abstract

The invention relates to a process for the preparation of * & exp2! Imidazolines, which have a significance as biologically active substances in pharmaceutical and other preparations. Such imidazolines should be readily synthesized from readily available compounds. According to the invention, N, N-ethylene-N'-arylamidines (1) are converted with HCl or HBr into N- & 2-chloro (bromo) ethyl! -N'-arylamidinium chlorides (bromides) and added with sodium hydroxide or potassium hydroxide solution 1,2-disubstituted * & exp2! Imidazolines (2) cyclized. With hydriodic acid arise from the amidines directly the * & exp2! -Imidazoliniumjodide. The salts of the * & exp2! Imidazolines with hydrohalic acids are shown. The invention can be used in the chemical industry. formulas

Description

232763 4

Process for the preparation of 1,2-disubstituted

2 z-imidazolines and their salts

Field of application of the invention

The invention relates to a process for the preparation of 1,2-

disubstituted δ-imidazolines of the general formula I.

R '

and their salts, where R is phenyl, substituted phenyl, tert-butyl or adamantyl (1) and R ^{1 is} phenyl or substituted phenyl, preferably alkyl, nitro or halogen.

2 substituted phenyl. These 1,2-disubstituted δ imidazolines and their salts are of interest as potential drugs.

Characteristic of the known technical solutions

It is known that Δ- imidazolines, especially 2- or 2,4-substituted, have a wide variety of biological activities, the main meaning being the effect on the cardiovascular system. (M.Hartmann, H. Isler, Naunyn-Schmiedebergs Arch. Exp. Pathol Pharmacol., 192 , 141 (1939); F. Hauschild, Pharmacology and Fundamentals of Toxicology, VEB Georg Thieme, Leipzig, 4.A-UfI., 1973 , 938-939, M.Negwer, Organic-Chemical Drugs and their Synonyms, vols 1-3, vol. 3 _f 1310 (imidazolines), Akademie-Verlag-Berlin 1978.)

Ο 4 ΑΙΙΠ HQOUUR / .OQfl

232763

Besides that, too. Δ imidazolines having sedative and / or antidepressant and various other biological effects. (M.Negwer, loc. Cit.)

ρ 1,2-Disubstituted Δ- imidazolines are studied to a lesser extent and have, for example, bacteriostatic and local anesthetic properties. (LPKyrides, FBZienty, GW Staehly, HLMorrill, J.org.Chemistry J2., 577 (1947).)

In DE-OS 2818367 1-alkyl-2-phenoxyalkyl-d ² -imide

azolines described as insecticides. Pur · 1,2-diamino-d-imidazolines an antihypertensive effect was found (DE-OS 2652923).

2 We know nothing about the antiviral properties of 1,2-disubstituted Δ imidazolines.

For the synthesis of 1,2-diaryl-4-imidazolines by isomerization of Ν, Ν-ethylene-N'-arylbenzamidinen by means of sodium iodide or potassium thiocyanate in acetone or i-propanol with heating of HWHeine and HS _o Bender (J.org.Chemistry 2g , 461 (196)) given two examples. This process has the disadvantage that a molar ratio of 1: 1 of the amidine to the isomerization-causing agent has to be kept favorable, to be carried out in the organic solvent and at its boiling point. The reaction time of 3 - 3.5 h increases with reduction of the sodium iodide to several days; with potassium thiocyanate are also given 47 h. The yields are very good.

According to US Pat. No. 3,165,529, a Ν, Ν-ethylene-N'-arylbenzaniidine is converted in ether with a concentrated solution of hydrogen chloride in i-propanol into an N- (2-chloroethyl) -N'-arylbenzamidine, which is filtered off, rapidly into water dissolved with less than an equivalent amount of sodium hydroxide in

2 nig of water. The formed δ- imidazoline is in 43 percent. Yield won.

N- (2-ChIOrBtIIyI) -N ¹ - 2 (3) (4) -benzamidine methoxyphenyl results in a corresponding Δ -Imidazoliniumchlorid (US 3 165529) in the treatment with hydrogen chloride in isopropanol. These compounds have diuretic, especially natriuretic properties,

- ³ - 232763

A disadvantage of this process is the use of organic solvents, the introduction of hydrogen chloride into the solvent and the use of elaborately prepared starting materials.

The possibility of isomerization of N, N-ethylene-N'-aryldiphenylacetamidine and of an isobutyramidine was also exploited by M. Murai and co-workers (J.org.Chemistry 42, 847 (1977)). They reacted these amidines with hydrochloric acid in relatively high ethanol for 5 h at the boiling point, then neutralized the reaction solution with sodium hydroxide solution and then obtained the corresponding Δ-imidazolines. There was no information on a biological activity of the compounds produced. Disadvantages of this process are the use of an organic solvent and working at elevated temperature. The yields are between 76 and 43 %. " The preparation of the starting amidines takes place by addition of aziridine to relatively difficult to access heterocumulenes, so that only aliphatic amidines can be detected by this process.

Object of the invention

The aim of the invention is to provide new

en, biologically active 1,2-disubstituted Δ- imidazolines and their salts, the synthesis of the reagents used sparingly, convenient to avoid organic solvents should be relatively fast and energy-saving in good yield feasible.

Explanation of the essence of the invention

The invention has for its object to develop a process for the preparation of 1,2-disubstituted δ-imidazolines and their salts, which allows the use of easily handled reagents, is not bound to an organic solvent and does not require elevated temperatures in a relatively short reaction time ,

According to the invention, e.g. a according to WP CO7C / 221921 easily accessible Ν, Ν, Ν'-trisubstituted amidine of general formula II

... 232763

NO'

in which R and R ^{1 have the} same meaning as in formula I, treated with a concentrated or diluted hydrogen halide-53 / i.ure HX with X = Cl, Br or J at room temperature, optionally with shaking, until the amount of any precipitating Precipitation no longer increased. This will require 1 h to a maximum of 3 h. Cheap acid concentrations are 8 - 32 percent. Hydrochloric acid, 40%. Hydrobromic acid or 40-50 percent. Hydriodic. In the reaction of the amidine with hydrochloric or hydrobromic acid, an N- [2-chloro-ethyl] -N'-arylamidinium hydrochloride or hydrobromide can precipitate, while the use of hydriodic acid unexpectedly immediately

Ilydrojodid a Δ imidazoline separates, which can be conveniently separated, cleaned in a conventional manner and can be converted by alkalization in the free base.

HX ^, NH-CH ₀ -CH ₀ X OH "ι > RC.

R-C

! HJ r ^ \ OH *

X = Cl, Br

The separation of said precipitated salts (N- [2-chloro (bromo) ethyl] -N'-arylamidinium halides) can be omitted in any case by the acidic reaction mixture for cyclization with an inorganic base, preferably with sodium or potassium hydroxide , carefully if necessary under cooling

_ C

.232763 4

alkalized, liberated 4-imidazoline is filtered off with suction and recrystallized or shaken out of the alkaline phase with a suitable solvent, for example with ether, methylene chloride or chloroform. After drying and concentration of the extract, the δ-imidazoline can also be isolated in very good yield. It is purified by recrystallization from a common solvent or solvent / water mixture.

For the conversion of the δ- imidazolines of the formula I into their hydrohalides, methods known per se are used, but the hydroiodides, as described above, can be obtained substantially more advantageously directly from the reaction mixture. Compared to the known syntheses process of the invention is more economical, because according to WP CO7G / 221921 conveniently available amidines used, is advantageously carried out in aqueous medium with easily dosed acids and bases and without energy, care must not be paid to exact equivalence ratios, and the 1 , 2-disubstituted

Δ- imidazolines and their hydrohalides are readily available in very good yield.

The inventive method is more economical because the hydrogen halides used are less expensive than previously used agents. Surprisingly, the ring closure to imidazoline directly caused by hydriodic acid is unknown, for which no comparable example is known. In addition, the isolation of an intermediate product can be dispensed with in the process according to the invention so that 4-imidazolines are obtained directly from the amidine used in the one-pot process in yields of 75 to 95 % and above.

The Δ- imidazolines prepared according to the invention and their salts unexpectedly exhibit an in vitro activity against viruses. Furthermore, an antiphlogistic effect was found.

embodiments

δ -imidazolines (Table 1)

- 6 Hethode A

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0.01 mol of a Ν, Ν-ethylene-N'-arylamidins is 1 - 3 h at room temperature in 20 - 50 ml 8 - 32-proz. Shaken hydrochloric acid, wherein the Hydroohlorid of an N- (2-chloroethyl) -N'-arylamidine precipitates, the isolation of which is not required. The reaction mixture is carefully mixed with conc. Alkaline sodium hydroxide, whereby the Imidazolinring closes. The precipitated salt can also be sucked or decanted off and with conc. Sodium hydroxide solution as further processed above

become ρ. In both cases, the δ- imidazoline separates oily and can be isolated directly after crystallization

become. If the δ- imidazoline does not crystallize, the extract is extracted by shaking with a suitable solvent, such as ether, for example over Na ₂ SO. or CaCl ₂ dried and concentrated. Recrystallize from ethanol, a mixture of ethane

nol / water, hexane or DMP / water, the Δ- imidazoline is obtained pure.

Method B

0.01 mol of an N, N-ethylene-N'-arylamidine is reacted at room temperature with 20 ml of 20-40 pFoz. Hydrobromic acid and shaken for 1 - 3 h. It is enough to shake occasionally. It is worked up as described under A. The precipitated salt, N- (2-bromomethyl) -N'-arylamidinium bromide, can be filtered off with suction or likewise processed further directly.

Method C

0.04 mol of hydroiodic acid (40-57%) are added at room temperature to 0.01 mol of a NjN-ethylene-N'-arylamidine.

P ben. It immediately crystallizes from a Δ -imidazoliniumjodid, which after alkalization with conc, potassium or sodium hydroxide solution provides the free base, or as described under A, isolated and can be further processed. After the reorganization

2, pure δ- imidazolines are obtained.

2 3 2 7 6 3 4

'J

Salts of a -imidazolines (Table 2)

a) The 1,2-disulfonate obtained by methods A, B, or C

Statuierten δ-imidazolines can be converted by conventional methods in their hydrohalides such as hydrochlorides, bromides or iodides.

b) According to method C, a Ν, ΪΓ-ethylene-N'-arylamidine is reacted with hydriodic acid. That at room temperature off

the reaction solution is crystallized Δ -Imidazoliniumjodid filtered off with suction, washed with ice-cold ethanol and recrystallized from ethanol.

Table 1

, 2 1,2-disubstituted A imidazolines of the formula I

R R ¹ Schmp. ⁰ C Payout {%) Metho de Lit. ^C 6 ^H 5 ^C 6 ^H 5 73-75 80 A 1,2,3 74 to 76.5 82 C ^G 6 ^H 5 4-NO ₂ -C ₆ H ₄ ' 174 76 A 2.4 4-NO ₂ -O ₆ H ₄ 4 -NO ₂ -G ₆ H ₄ ^C 6 ^H 5 4 -CH ₃ -G ₆ H ₄ 101-104 116-117.5 83 80 A A 4-NO ₂ -G ₆ H ₄ 3-GH ₃ -G ₆ H ₄ 117-118 84 A 4-1TO ₂ -G ₆ H ₄ 4-Cl-G ₆ H ₄ 127-129 91 A 4-NO ₂ -G ₆ H ₄ 3-Cl-C ₆ H ₄ 131-132 90 A (CH ₃ ) ₃ 3-CH ₃ C ₆ H ₄ 89 to 90.5 95 B (CH ₃ ) ₃ ^C 6 ^H 5 93.5 to 95.5 95 B C ₁₀ H ₁₅ ^G 6 ^H 5 89 to 90.5 95 A

Table 2

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2 1,2-disubstituted Δ-imidazolinium halides

RR ^f HX mp ° C Yield (%)

G ₆ II ₅ C ₆ H ₅ HJ 219-224 (Zers.) 75

C ₆ H ₅ C ₆ H ₅ HBr 150-160 (decomp.)

C Ala C / .H _C HCl 225-227 (dec.) 70

3-CH ₃ -G ₆ H ₄ (CH ₃ J ₃ C HCl 224-225.5 (dec.) 64

CrIU (CH 2) - C HCl 23Ο-24Ο (dec.) 53

1) I. Perillo and S. Lamdan, J. lieterocycl. Chem. 1970, 2 (4), 791; cit.n. GA 1970 , 77139g.

2)! 'IWPartridge and HATurner, J. Chem. Soc. London 1949 . 1308

3) K.-H. Wunsch, H. Dettmann and S. Schoenberg, Chem. 102 , 3891 (1969).

4) H.Heine and H ₀ S.Bender, loc.cit ..

Claims (2)

- ⁹ - 232763 A invention claim A process for the preparation of 1,2-disubstituted A ² -imidazolines of general formula I and their salts, wherein R is phenyl, substituted phenyl, tert-butyl or adamantyl (1) and R 'is phenyl or substituted phenyl, preferably represents alkyl-, nitro- or halogen-substituted phenyl, characterized in that a Ν, Ν-ethylene-N ¹ -arylamidin the general formula II with the for R and R ¹ _ττ reacted with a concentrated or diluted Ilalogenwasserstoff acid HX with X = Cl, Br or J at room temperature, optionally with shaking, optionally with a precipitate, according to the acid used HX, consisting of an N- [2-chloro (bromo) - ethylj-N'-arylamidine hydrochloride (hydrobromide) or a δ-imidazolinium iodide precipitates, the reaction mixture is then carefully isolated without separation of this precipitate, optionally with cooling, with an inorganic base, preferably sodium or potassium hydroxide solution alkalized, liberated Δ-imidazoline, purified or extracted from the reaction mixture with a suitable solvent, after drying and concentrating the extract, isolated from the residue thereof and purified or the precipitate separated off, 2 treated with inorganic base and liberated released Δ-imidazoline in the same manner and purified and optionally subsequently added in a conventional manner with a hydrohalic acid in a solvent or water.