DD149070A1 - METHOD FOR THE PRODUCTION OF BASIC SUBSTITUTED ACYLAMINEOHETEROCYCLES - Google Patents

Abstract

The heterocyclic compounds of this class are important as local anesthetics, pesticides and plant growth regulators. The aim of the invention is a one-pot process for the preparation of acylaminoheterocycles whose acyl group is substituted in the alpha position by a secundaeren cyclic amine radical of the formula I. By reacting a heterocyclic amine with an alpha-haloacyl halide, wherein an auxiliary base can be used, and a secundaeren cyclic amine is obtained a compound of the above general formula. The intermediaer resulting, physiologically strong alpha-Halogenacylaminoheterocyclen be not isolated. Various alpha-Halogenacylaminoheterocyclen, which would cyclize immediately in the isolation and thus would not be available to the conversion with a secundaeren cyclic amine, are also converted into compounds of formula I according to our one-pot process.

Description

Title of the invention:

Preparation of basic substituted acylamino heterocycles

Field of use:

Acylaminoheterocycles whose acyl group in (Ay position substituted by a secondary amine radical can be used as Lokalanaesthetica, fungicides, herbicides and plant growth regulators »

Characteristic of the known methods:

The hitherto known process for the preparation of basic substituted acylaminoheterocycles of the formula I,

R ₁ -M -CO-CH-R ₂

^S 3

where R ₁ = heterocycle,

R ₂ = hydrogen, alkyl radical,

Ro = secondary amine radical,

are basically based on two-stage syntheses. In the 1st stage, an aminoheterocycle is reacted with an O- haloacid carboxylic acid halide or halocarboxylic acid ester and the haloacylaminoheterocycle is isolated. Further reaction of the 10-haloacylaminoheterocycle with a secondary amine gives a compound of the formula I. by PN BHARGAVA and PR Singh, J. Indian Chem. Soc. 37 (1960) 241, 3H and K.IT. GAIND, Indian J. Chem. Soc. 5 (1967) 524 prepared some basic substituted acetylaminoheterocycles of the formula I »

Some other α-haloacylamino heterocycles which would be useful in the preparation of Porrael I compounds have been described by H. PIITGER and P. KRAPT Ber. dt sch. Ges. Ges. 57 (1924) 1952, A.E. Chitschibabin, ibid. 57 (1924) 2098; G. BEMiELHAMMER, S. DU BEREUIL, R.W. YOUNG, J. o. Rg. Chemistry 26 (1961) 2287; Canad. Patent 736883/15 »10 * 1958; A. KREUTZBERGER and B. MEYER, Archiv der Pharmazie 307 (1974) 281.

Deficiencies of Zweistufenverfahrene are the following?

a) The isolated haloacylaminoheterocycles are physiologically very aggressive and lead to prolonged use of allergies, which make further work with these compounds problematical ©

b) The work connected with the isolation of the haloacylaminoheterocycles is time-consuming and material-consuming.

c) Various isolated haloacylaminoheterocycles are rearranged and are no longer suitable for the production of titanium compounds. »

Object of the invention

The aim of the invention is a process for the synthesis of acylaminoheterocyden whose acyl group is substituted in O ^ -St ellung by a secondary cyclic amine radical (Pormel II) as a one-pot process in which an isolation of the toxic Halogenacylaminoheterocyclen deleted.

Hat-HH-CO-CH-R

I II

cycl. Arain

The new process also permits the preparation of compounds of formula II which, according to the two-stage process, yield other end products, e.g. B. starting from 2- or 3 ~ aminopyridine or 2-aminopyrimidine.

Explanation of the essence of the invention

The invention provides a one-pot process for the preparation of acylaminoheterocycles whose acyl group is substituted in the. ^ -Position by a secondary cyclic amine radical (formula II) which have local anesthetic, fungicidal, herbicidal or plant growth regulatory effects.

In formula II stand for Hot. the following groups: the pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, quinol-2-yl, quinol-3-yl-i quinol-4-yl, acridine ~ 9- yl, pyrimidin-2-yl, pyrazinyl, 1,2,4-triazinyl, -IrI, pyrazol-3-yl, 1,2,4-triazol-3-yl, 1,2,4 --Triazol-4-yl ~ and tetrazol ~ 5-yl group, also the thiazol-2-yl "- or in the 4- and 5-position once or twice by methyl, ethyl, phenyl, chlorophenyl, C ₁ -C ₂ -alkylphenyl, C ₁ -C 6 -alkylthio, C ₁ -TG ₂ -alkoxy or "chloro-substituted thiazol-2-yl group, the benzothiazol-2-yl or those in 4", 5, 6 and 7 Position once or more than once by methyl, ethyl, phenyl, halophenyl, C ₁ -C 6 -alkylphenyl, C ₁ -C ₂ -alkoxy, C ₁ -C 6 -alkylthio or chlorine-substituted benzothiazol-2-yl group, the benzimides "sol-2 -yl- bzv /, which in 4 ~, 5- »6- and 7-position by methyl, ethyl, Cj-Cg-alkoxy, C ₁ ~ C ₂ ~ alkylthio or chlorine bz / e bromine-substituted benzimidazole-2 -ylarup, the benzthiadiazol-4'-yl and the pyrid-3-oxy-pheny! group. R in formula II is hydrogen, the methyl bzv /. Ethylresto

Cycl. Aiain in formula II the pyrrolidino, piperidino, Hexamethylenimine-, liorpholino-, piperazino, L-Prolino-, benzimidazol-1-yl ~ 1.2 _s 3J4 ~ tetrahydro-quinol-1-yl, 1, 2,3j4-tetrahydro-isoquinol-2-5''i-. _> 2o-3-dihydro-indol-1-yl and 1,3-dihydro-isoindol-2-yl-Resto

- 4 * 2 19052

Our process for the preparation of acylaminoheterocycles whose acyl group is substituted in the <*> position by a secondary cyclic base (formula II), is that an amino-heterocycle of formula III

HeU-NH ₂ III

where Het. = Het. Forme1 II, in a solvent such as benzene, toluene, acetone, tetrahydrofuran, dioxane or chloroform with a <x> -halogencarbonsäurehalogenid of formula IV,

X-CO-CH-R "IV

wherein X = Cl or Br and R '= R ¹ is added under stirring at a temperature of -10 to +10 ⁰ C, in formula II. in the cold Thereafter, 3 moles of the secondary cyclic amine of the formula V,

H-cycl. Amine V

where cycl. Amine = cycl. Amin in Fo ^ anel II means, dissolved in a solvent mentioned for the above reaction, added dropwise. Thereafter, it is stirred for 1-2 hours at room temperature and then for 5-8 hours at the boiling point of the solvent. In a variant of the process, the hydrogen halide formed in the reaction of the heterocyclic amine with the <Al- halocarboxylic acid halide can be salt-bound by adding an auxiliary base, such as triethylamine or pyridine. The salt is removed after the reaction. Thereafter, 2 moles of the secondary cyclic base are added as indicated above and correspondingly far erver driven,

embodiments

Example 1: 3-Piperidinoacetyl-aminopyridine A solution of 9.4 g (0.1 mol) of 3-aminopyridine in 200 ml of dry benzene was added dropwise with stirring and ice-cooling with 11.2 g (0.1 mol) of chloroacetyl chloride in 50 ml ml of dry benzene. 25.5 g (0.3 mol) of piperidine were added dropwise to the resulting suspension. The mixture was stirred for 2 hrs. In an ice bath, allowed to stand at room temperature for 2 hrs and then refluxed for 6 hrs. After cooling, the piperidine hydrochloride was filtered off with suction. The filtrate was freed from the solvent under reduced pressure and the residue was recrystallized from η-hexane

Mp: 52-53 ° yield: 15.3 g (70 % of theory )

Example 2 4-Piperidinoacetylamino-pyridine Analogously to Example 1, 14.1 g (0.15 mol) of 4-aminopyridine, 15.3 g of chloroacetyl chloride and 38.2 g of piperidine were refluxed for 5 hours. »Mp 58 - 59 ° from n-decane Yield: 24.6 g (75 %)

d. Th.)

Example 3 2-Piperidinoacetylaminothiazole Analogously to Example 1, from 10.0 g of 2-aminothiazole, 11.2 g of chloroacetyl chloride and 25.5 g of piperidine. It was refluxed for 5 hrs.

Mp: 87-90 ° from n-heptane Yield: 15.7 g (70 % of theory )

Example 4: 2-Piperidinoacetylaminobenzothiazole 11.2 g were added to a solution of 15.0 g (0.1 mol), 2-aminobenzothiazole and 10.1 g (0.1 mol) of triethylamine in 100 ml of tetrahydrofuran in an ice bath Added dropwise (0.1 mol) of chloroacetyl chloride. After removing the ice bath, stirring was continued until the acid chloride odor practically disappeared. "

The precipitated triethylammonium chloride was filtered off with suction. 17.2 g (0.2 mol) of piperidine were added dropwise to the filtrate at room temperature with stirring and then refluxed for 4 hours. The piperidine hydrochloride was filtered off with suction from the cooled reaction mixture, and the filtrate was concentrated to dryness in vacuo the residue was recrystallized from n-butanol, the crystals being washed with a little ethanol. M.p .: 133-134 ° yield. 19.8 g (72 % of theory )

Example 5: 2-Pyrrolidinoacetylaminobenzothiazole Analogously to Example 4. Instead of piperidine, 14.2 g of pyrrolidine were used.

Schrap .: 63-65 ° from n-pentane yield 10.4 g (40 % of theory )

Example 6 2-Hexamethyleneiminoacatylaminobenzothiazole Analogously to Example 4. Instead of piperidine, 19 g of hexamethyleneimine were used.

Mp: 45-48 ° from acetone / water Yield: 24 g (85% of theory)

Example 7 2-Piperidinoacetylamino-6-methoxybenzothiazole Analogously to Example 4. Instead of 2-aminobenzothiazole, 19.0 g of 2-amino-6-raethoxybenzothiazole were used. Melting point: 118-119.5 ° from alcohol / yre yield: 28 g (95 % of th.)

Example 8: 2-Piperidinoacetylamino-4-chlorobenzothiazole Analogously to Example 4. 18.4 g of 2-amino-4-chlorobenzothiazole were used instead of 2-aminobenzothiazole. Mp: 172-173.5 ° from n-butanol. Yield: 11.4 g (37 % of theory )

Example 9: 4-Hexamethyleneindioacetylamino-phenyl-pyridine

3-yl ether

Analogously to Example 4. Instead of Aminobenzthiazol 18.6 g of 4-iiMnophenyl-pyrid-3-yl-ether and instead of piperidine 19.8 g of hexamethyleneimine were used, mp. 67 - 69.5 ° from acetone / water. Yield: 16.9 g (53 g d. Th.)

Example 10: 2 ~ (^ -pyrxolidinopropionylamino) -6-raethoxy

benzothiazole

To a solution of 19.0 g (0.1 mol) of 2-amino-6-methoxybenzothiazole and 10.1 g (0.1 mol) of triethylamine in 100 ml of tetrahydrofuran were added in an ice bath with stirring 21.5 g (0.1 Mol) of α-bromopropionyl bromide added dropwise. After removal of the ice bath, stirring was continued until the acid smell had practically disappeared. The precipitated Triethylammoniunibromid was aspirated. The filtrate was added dropwise at room temperature with stirring with 14.2 g (0.2 mol) of pyrrolidine and then heated to reflux for 4 hrs. The pyrrolidinium bromide is filtered off with suction, the filtrate is evaporated to dryness in vacuo and the residue is recrystallized from petrol

M.p. 74 - »79 ° Yield: 18 g (62 % of theory )

Example 11: 2 - (^ -pyrrolidinobutyrylamino) J-o-methoxy

benzothiazole

The compound was obtained analogously to Example 10, if instead of the <6-Brompropionylbromids 22.9 g °° -Brombutyrylbromid were used.

Mp: 83-85 ° from n-decane Yield: 25.6 g (86 % of theory)

Claims (4)

Claims. , 1.) Process for the preparation of basic substituted acylaminoheterocycles of the formula II, Het-HH-CO-CH-R ¹ I II cycl.Amin where Het. the following groups are: pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, quinol-2-yl, quinol-3-yl, quinol-4-yl, acridine -9-yl, pyrimidin-2-yl, pyrazinyl, T, 2,4-triazin-3-yl, pyrazol-3-yl, 1,2,4-triazol-3-yl, 1 , 2,4-triazol-4-yl and tetrazol-5-yl group, likewise the thiazol-2-yl or in the 4- and 5-position once or twice by methyl, ethyl, chlorophenyl, C, -Cp-alkylphenyl, Cj-Cp-alkylthio, Cj-C ₂ -alkoxy ^ Zw. Chloro-substituted thiazol-2-yl group, the benzothiazol-2-yl or in the 4-, 5-, 6- and 7-position one or more times by methyl, ethyl, phenyl, halophenyl, C.-Cp-alkylphenyl , Cj-Cg-alkoxy, C -, - Cp-alkylthio or chlorine-substituted benzothiazol-2-yl group, the benzimidazol-2-yl-, or in the 4-, 5-, 6- and 7-position by methyl , Ethyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio or chloro or bromo-substituted benzimidazol-2-yl group, the benzothiadiazol-4-yl and the pyrid-3-oxy-phenyl group. Y / eiterhin R 'for hydrogen, methyl and. Ethyl and cycl. Amines for the pyrrolidino, piperidino-Hexaiüethyleniiiiino-, Llorpholino-, L-prolino, benzimidazol-1-yl or 1,2,3,4-tetrahydro-quinol-i-yl, 1,2,3,4 Tetrahyro-iso-quinol-2-yl, 2,3-dihydro-indol-1-yl and 1,3-bihydro-isoindol-2-yl radical, characterized in that a heterocyclic amine of the general formula III . , Het-HH ₂ III Het.-Het. in formula II, in a one-pot proceed successively with a halocarboxylic acid halide of general formula 17 X-GO-CH-R ' I? wherein X is chlorine or bromine and R ¹ = R ¹ in formula II, and a secondary cyclic Amiη the general formula V, H-cycl. Amine V where cycl. Amine = cycl. Amine in formula II is reacted in an inert solvent in the cold. An auxiliary base can be used. Subsequently, the reaction mixture is heated. 2.) Process according to item 1, characterized in that inert solvents such as benzene, toluene, acetone, tetrahydrofuran, dioxane and chloroform are used. X 3) The method of item 1, characterized in that the reaction of the heterocyclic amine of the formula III with an a ~ -Halogencarbonsäurehalogenid of the formula IV between - 10 ⁰ C and +10 ⁰ C is performed. 4o) Method according to item 1 and 3, characterized in that an auxiliary base such as triethylamine, pyridine or dimethylaniline is used for the reaction. 5.) Process according to item 1, characterized in that the further reaction of an intermediate with a secondary cyclic amine of formula V between -10 ⁰ C and the boiling point of the solvent used is carried out. 6.) Process according to item 1, 4 and 5, characterized in that at most 3 moles, when using an auxiliary base at most 2 moles of secondary cyclic amine, based on the heterocyclic amine used.