DE2110227A1 - Process for the preparation of five- or six-membered heterocycles - Google Patents

Description

2110227 FARBENFABRIKEN BAYER AG

LEVERKUSEN-Beyerwerk - 3 Μ§ΓΖ 1971 Patent department PS / ΜΗ

Process for the preparation of five- or six-membered heterocycles

The invention "relates to a method for the production of five- or six-membered heterocycles of the general formula I.

-NH-R ²

wherein

A is a bivalent, unsubstituted or substituted, straight-chain or branched aliphatic, cycloaliphatic, araliphatic or aromatic radical, the in particular by halogen, cyano, nitro, amino, hydroxy, ether, thioether, ester and / or SuI- fonyl groups can be substituted,

2 X = O, S or, if A is not an aliphatic radical, also NR,

R and R ¹ = H, halogen, nitro, aliphatic, cycloaliphatic, araliphatic or aromatic radicals, in particular by halogen, nitro, (tert.) Amino, hydroxy, ether, thioether, ester and / or sulfonyl -Groups can be substituted and / or linked to one another in a ring,

R ² = H, an aliphatic, cycloaliphatic, araliphatic or aromatic radical which can be substituted in particular by halogen, nitro, (tert,) amino, hydroxy, ether, Tliioether, ester and / or sulfonyl groups ,

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and η represent an integer from 2-15, where the as

- (G- defined carbon chain heteroatoms

Vi ¹ Zn

and / or substituted or unsubstituted divalent ones (Het) arylene radicals, for example phenylene, naphthylene, diphenylene, α, β- or β, β'-thienylene, at, β- or β, y_pyridylene or pyrazinylene or pyrimidinylene, and / or contain double or / and triple bonds can,

or dimolecular compounds of the formula given above,

1 2 wherein the linkage via A, R, R, R or via the in the up through

'R η

defined aromatic or unsaturated carbon chain Remainder takes place, whereby the respective link is included only once in the formula.

A number of compounds of this type are already known; In particular, these are derivatives of the general formula given above, in which X = NR ₂ or S, and in which the carbon chain defined by η is usually small, ie has predominantly only 1 to 3 carbon chain links.

As a rule, o-diamines or o-aminothiols are used to represent these compounds on the one hand with ^ -amino acids, in which the amino group is protected or unprotected and the carboxyl group as such or in the form of its nitrile or Acid chloride is present, or with halogen or unsaturated Carboxylic acids condensed, in the latter case the aminogmpp © by aminolysis of the haloalkyl group, if appropriate according to Gabriel, or addition of ammonia or amine to existing double bonds.

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For example, according to German Patent 1,131,688 and British Patent 1,023,792 2-63-aminoalkyl-benzimidazoles, Japanese Patent 22,389 (1966) and Chem. Pharm. Bull. (Tokyo) 13, 180- 8 (1965) 2-Aminoäthyl-thiazoline and according to Z. obsc. Chim. 32y. 3703-7 (1962) and ^ _x 1926-30 (1964) 2-amino = methyl or 2-aminoethyl-benzothiazole accessible.

63-aminocarboxylic acids are often obtained industrially from easily accessible lactams by saponification. The aim of the present invention is consequently to produce heterocycles of the general formula I given above not via the detour of hydrolytic cleavage of lactams to <ü-aminocarboxylic acids _f but directly from corresponding lactam derivatives with simultaneous ring opening.

It has been found that there are generally five bcw. six-membered heterocycles of the formula I given above can be prepared conveniently and in good yields by using 1,2- or 1,3-aminothiols, 1,2- or 1,3-aminohydroxy compounds or aromatic or araliphatic diamines (II) with reactive cyclic imines (III) or the amide compounds (VI) in the melt of the components or optionally dissolved or suspended in suitable solvents at lemperatüren from -20 ⁰ C to 300 ⁰ O, O preferably from ⁰ C to 200 ⁰ C, is reacted.

The reactions can be illustrated using the following formulas:

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(CRR ¹ )

(CRR ¹ )

N
H

II

III

IV

V A

(CRR ¹ )

-HT -HZ

II

VI

VII

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In these Arabic words:

A is a bivalent, urisubstituted or substituted, straight-chain or branched aliphatic, cycloaliphatic, araliphatic or aromatic radical, which is in particular replaced by halogen, cyano, nitro, (tert.) Amino, hydroxy, ether, thioether, ester and / or sulfonyl groups can be substituted,

2 X = O, S or, if A is not an aliphatic radical, also NR,

1
R and R = H, halogen, nitro- _t aliphatic, cycloaliphatic, araliphatic or aromatic radicals, in particular by halogen, nitro, (tert.) Amino, hydroxy, ether, thioether, ester and / or sulfonyl groups may be substituted and / or linked to one another in a ring,. '

m

R = H, an aliphatic, cycloaliphatic ^ araliphatic ^ i or aromatic radical which is substituted in particular by halogen, nitro, _l (tert) amino, hydroxy, ether, thioether, ester and / or sulfonyl groups can be,

η is an integer from 2 to 15, where the by

nated carbon chain heteroatoms and / or substituted or unsubstituted divalent (Het ~) arylea- * residues, for example phenylene, naphthylene, diphenylene, α, β- or β, β'-thienylene, oc, ß- or ß, ^ * - pyridylene or Pyrazinylene or pyrimidinylene, and / or can contain double or / and triple bonds, ϊ a nucleofugic leaving group, in particular halogen,

OPOCl ₂ , OPOl ₂ , OSO ₂ Cl, OSOCl, OSO ₂ R ³ , OCOCl, OCOR ³ ,

and-N (CW, where R ^{5 is} a (low)

Represents alkyl or aryl radical,

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Z = Y, when Y is halogen, OR ⁵ or SR ³ , and Z is in particular OPCl ₄ , OPOCl ₂ , OPCl ₂ , OSO ₂ Cl, OSO ₂ R ⁵ , OCOCl, OCOR ^3,. when Y - is halogen, where R ^{3 is} an alkyl or aryl group,

and also the formulas I, II, III, V, VI and VIII mentioned dimolecular compounds of the same formula, in which the linkage via A, R, R, R or by the in the above Aromatic or unsaturated radicals contained by η defined carbon chain takes place, the respective Link is only included once in the formula.

The present invention thus provides a process for the preparation of five- or six-membered heterocycles of the general formula _Λ

^R \

A> C] - NHR ⁴ I, wherein

A is a bivalent unused or substituted, aliphatic, cycloaliphatic ^ araliphatic ^ or aromatic residue is

2 X 0, S or, if A is not an aliphatic radical, NR,

R and R ^{1 are} hydrogen, halogen, nitro, aliphatic, cycloaliphatic, araliphatic ^ and / or aromatic radicals which can be identical or different and which can be linked to one another in a ring,

R ^{2 is} hydrogen, an aliphatic, cycloaliphatic ^ araliphatic or aromatic radical and

η represents an integer from 2-15,

where the carbon chain defined as - C -

if heteroatoms and / or substituted or unsubstituted divalent hetarylene or / and arylene radicals and / or double or / and Contains triple bonds.

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It is known from US Pat. No. 3,399 "that lactim ethers react with ethylenediamine or with trimethylenediamine to form 2- (5'-aminopentyl) -imidazoline or 2- (5'-aminopentyl) -tetrahydropyrimidine. However, the reaction was limited on the one hand only 5- to 8-ring lactime ethers, on the other hand purely aliphatic diamines. It was therefore not to be expected that hydroxyamines or mercaptoamines according to the process of the present invention with lactime derivatives would surprisingly dissolve the lactam-carbon-nitrogen- Binding and new formation of a carbon-sulfur bond or carbon-oxygen bond or the less reactive aromatic diamines would enter into the same rearrangement reaction. Furthermore, it is surprising that the cyclic amide compounds (VI) ₁ also undergo the known ring splitting reactions in both the Saponification and also in the polymerization are very difficult to access, according to the inventive method gla tt react with ring opening to form the monoamino-substituted heterocycles. The specification for the preparation of 2- (<δ-aminoalkyl) -imidazolines or -tetrahydropyrimidines listed in American patent 3 399 cannot be the basis of a technical process Working up the reaction products 12 to 50 times the volume of dietary ether in order to separate off any by-products, and thus a considerable effort.

By contrast, according to the process according to the present invention, the use of reactive cyclic imines or cyclic amide - compounds - which are technically particularly

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c -rs simply from N-unsubstituted or -substituted -aatamen and certain acid chlorides - preferably also 'in situ' - are accessible, a considerable technical Progress.

Any aromatic compounds can be used for the process according to the invention or araliphatic 1,2- or 1,3-Mamine suitable, the maximum may be mono-substituted on an amino group, for example:

o-Phenylenediamine, 4-methyl, fluorine, chlorine, bromo, methoxy, phenoxy, jiI tro, methyl, trifluoromethyl, ethyl, cyclohexyl o -phenylenediamine, 4,5-dimethyl-, -dichloro-, -dibromo, -dimethoxy-o-phenylenediamine, trichloro-o-phenylenediarain, N-methyl-, N-cyclohexyl-, N-phenyl-o-phenylenediamine, N Ethyl-4-chloro-o-phenylenediamine, 1,2-diaminonaphthalene, 2,3-diaminonaphthalene, diaminoanthracene, 9,10-diaminophenanthrene, diaminoanthraquinone, N-methyldiamino-naphthalene, N-phenyl-diamino-phenanthrene , 3,4-diaminothiophene, 3,4-diaminofuran, 5,6-diaminothionaphthene, 5,6-diaminocumarone, 3,4-diaminopyridine, 4,5-diaminopyrldazine, 2-aminomethylpyrrole, N-ethyl-3 _f 4-diaminothiophene , N-phenyl-5,6-diaminothionaphthene,

o-aminobenzylamine, o-amino-e ^ dC-dimethylbenzylamine, o-amino- <jC, C £> -diphenylbenzylaml.n, o-amino-p-hydroxybenzylamine, o-aminop-methoxybenzylamine, o-amino-p-carbethoxybenzylamine, I-aminos methyl-2-amino-naphthalene, 2-aminomethyl-3-amino-naphthalene, 1,8-diamino-naphthalene, 1-aminomethyl-carbazole, 3-aminomethyl-4-aminothiophene, 3,4-diamino-thlonaphthene, o- (N-Methylamino) -benzylamine, o-Amlnobenzyl-methylamine, o-aminomethyl-diphenylamine, o-aminobenzyl-benzylamine, 1-ethylamino-8-aminonaphthalene, 3-aminomethyl-4-butylaminothiophene.

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Suitable bis-diamines according to the invention are, for example: 1,2,4,5-tetraminobenzene, 1,4-bismethylamino-2,5-diaminobenzene, 3,3'-diaminobenzidine, 3,3 ', 4,4 ^I- tetraminodiphenyl ether , cc, oc-bis (m, p-diaminophenyl) -p ^ diisopropylbenzene.

As aminothiols are suitable for the process according to the invention any, for example:

Cysteamine, 2-mercapto-4- * aminohexane, "i-amino-3-mercapto-decane, 2-phenyl-2-mercapto-ethylamine, 2-chlorophenyl-2-mercaptoethylamine, 2-p-aminophenyl-i-meroapto- ethylamine, 2-p-methyl = mercaptophenyl-i-mercapto-ethylamine, oc-amino-ß-mercaptopropionic acid ethyl ester, 2-mercapto ~ cyclobutylamine, 2-mercaptocyclohexylamine, 2-mercapto-cyclodecylamine, 2-mercapto-3-butyl = oxy -propylamine-1, o-aminothiophenoi, ο, ρ-liaminothiophenol, p-hydroxy-o-aminothiophenol, dimethylamine »·} trifluoromethyl-, chloro-, bromo-, dichloro- ^, trichloro-, cyano-, acetyl-, benzoyl -, carbethoxy, nitro, methoxy, phenoxy, nitro, methyl, isopropyl, tert-butyl, cyclohexyl, phenyl, dimethyl-o-aminothiophenol, i-amino-2-mercapto-naphthalene , 1-mercapto-2-amino-naphthalene, 2-amino-3-mercapto-naphthalene, i-amino-2-mercapto-anthracene, 9-amino-IO-meroapto-phenanthrene, 3-amino-4-mercapto-pyridine, e-amino-T-mercaptoquinoline, 4-amino-5-mercaptoindole, 3 "= 'amino-4-mercapto-furan, 3-amino-4-mercaptothiophene, 5-amino-6-mercaptothio naphthene, 3-mer = captopropylamine, 1-phenyl ~> 3-inercaptopropylamine, 2-methoxy-3-mercaptopropylarain _s ^ -amino - ^ - methyl mercaptobutyrate, y-amino - ^ - mercaptonitrxls 3-mercaptocycloootylamine, 3-mercapto = cyclododecaptylamine , 3-mercaptostearylamine-1, o- (mercaptomethyl) -aniline, o- (aminomethyl) -thiophenol, 3-chloro-, 3,4-mchloro-o- (mercaptomethyl) -aniline, 3-trifluoromethyl-, 3-nitro -, 3-cyano-, 3-ethoxy-o- (mercaptomethyl) -aniline,! - (mercapto = methyl) -2-naphthylamine, i-mercapto-8-aminonaphthalene, 3-amino-4-mercaptomethylthiophene, 3-mercapto -4-aminoindole, 4-mercapto-5-aminoquinoline, 3-amino-4-mercaptothionaphthene.

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Bis-aminothiols useful in the process of the invention are for example:

1,2-diamino-4,5-dimercaptobenzene, 1,4-diamino-2,5-dimercapto = benzene, 3,3'-dimercaptobenzidine, 1,5-dimercapto-2,6-diamino = naphthalene, 3,3'-dimercapto-4,4'-diaminodiphenyl ether.

Furthermore, any aminohydroxy compounds are suitable for the method according to the invention, such as aminoethanol, 1,2-aminopropanol, 1,2- and 2,3-Aihinobutanol, 3-aminohexanol-4, 2-aminooctanol-1, 2-hydroxy-3- πlethoxy-methyl-äthylaπlin, a-amino-ß-hydroxypropionic acid ethyl ester, 2-amino-2-phenyl = ethanol, 2-amino-i-chlorophenyl-ethanol, 1-methoxyphenyl-2-aminopropanol-1, 2-amino 2-methylbutanol-1, 2-aminocyclo = hexanol, 2-aminocyclooctanol, 2-aminocyclododeeanol, 2-aminophenol, 4-chloro-2-aminophenol, 4-chloro-5-nitro-2-aminophenol, trifluoromethyl, methyl, Methoxy, methyl = mercapto, cyano, acetyl, benzoyl, carbethoxy-2-aminophenol, 1-amino-2-naphthol _s 2-araino-1-naphthol, 2-amino-3-naphthol, 9- Amino-IO-hydroxyphenanthrens 3-amino-4-hydroxypyridine, 6-amino-7-hydroxyquinoline, 4-amino-5-hydroxyindole, 3-amino-4-hydroxythiophene, 5-amino-6-mercaptothionaphthene; 3-aminopropanol, 3-aminobutanol-1, 3-aminodeoanol-1, i-phenyl-3-hyclroxypropylamine, 2-amino-4-hydroxybutyric acid ethyl ester, 2-ethoxy-3-hydroxypropylamine; o- (Hydroxymethyl) -aniline, o- (aminomethyl) -phenol, 3-chloro-, 3,4-dichloro-, 3-trifluoromethyl-, 3-methoxy-, 3-cyano-o- (hydroxymethyl) -aniline , 1-Hydroxymethyl-2-naphthylamine, i-Hydroxy-8-ainonaphthalene, 3-Amino-4-hydroxymethylthiophene, 3-Hydroxy-4-aminoindole, 4-Hydroxy-5-aminoquinoline, 3-Amino-4.-hydroxythionaphthene .

According to the invention, suitable bis-aminohydroxy compounds are suitable for example

1,2-diamino-4,5-dihydroxybenzene, 1,4-diamino-2,5-dihydroxy = benzene, 3 _ff 3'-dihydroxybene in _t 1,5-dihydroxy-2,6-diamino = naphthalene, 3.3 ^i- Dihydroxy-4,4 ^t -diamino-diphenyl ether.

-10-

Suitable underlying the activated lactam derivatives Lactams according to the method of the invention are, for example, the following:

3-propiolactam, 3-phenyl-, 3,3-diphenyl-, 2, 3-diphenyl-, 3-methyl-, 3-ethyl-, 3-benzyl-, 3,3-dimethyl-, 2,3, 3-trimethyl-propiolactam, 4-butyrolactam, 5-valerolactam, 6-caprolactam, di-chlorocaprolactam, AE Nitrocaprolactam, the QC-to ^ -Methylcaprolactame that OC- ^ to -Phenylcapro = lactams <K to c -Carbethoxycaprolactams, 7-enantholactam, 8-capryllactam, 12-laurolactam, naphthostyril, phthalimidine, morpholone, benzmorpholone, octahydroquinolone-2, 7-0xo-4-methyl = hexahydro-1,4-diazepine, 1H-2-oxo-2 -ethyl-1, i-diazacyclooctane, 2-0x0-5,6-benz-tetrahydroazepine; y ^ y'-biscaprolactam, methylenebiscaprolactam,>",>"'- isopropylidene biscaprolactam.

Lactams indicated above as substituents linked to the lactam nitrogen are for the reaction according to the invention For example, residues are suitable, such as:

Methyl, ethyl, vinyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, crotyl, hexyl, decyl, cyclopentyl, Cyclohexyl, cyclohexenyl, oyanethyl, cyanhexyl, chloroethyl, cyanhexyl, chloroethyl, trifluoromethyl, ethoxyethyl, dimethyl = aminoethyl, carbethoxyethyl, butylmercaptopropyl, benzyl, (^, oc-dimethylbenzyl, phenethyl, phenyl, fluorine, trifluorine, Chlorine, dichloro, trichloro, pentachloro, bromine, iodine, Nitro, dinitro, cyano, methoxy, phenoxy, methyl mercapto, Carbethoxy, acetyl, benzoyl, dimethylamino, methyl, Dimethyl, tert-butyl, nonyl, trifluoromethyl, trichloro = methyl-, hydroxyphenyl, naphthyl, thiophenyl, oxazolyl, Benzoxazolyl, thionaphthenyl, indolyl, pyridyl, quinolyl, Isoquinolyl;

Methylene, ethylidene, isopropylidene, benzylidene, ethylene, 1,2-propylene, 1,3-propylene, hexamethylene, cyclohexylene, Phenylene, naphthylene, diphenylene, phenanthrenylene.

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la the babble, where the reactive terminations of the formulas (III) or «(¥ 1) represent isolable defined substances, they can be used al® such in the reaction according to the invention. Connections of this type are for example:

Lactim (cjclo) alkyl ethers, lactim aryl ethers, lactim thio (cyclo) = alkyl ethers, lactim thioaryl ethers, lactam dialkylacetals, laetam diarylacetals, laotam mercaptals, dilactim ethers, anhydrodilaotams _s lactim chlorides, lactam chlorides.

Reactive compounds of the formulas (III) or (71) for the purposes of the invention can, however, also be prepared in situ and reacted further without intermediate isolation. For this purpose, the lactams given above are treated - if appropriate in the presence of suitable inert solvents or if appropriate in the presence of X ⁵ On certain acid-binding agents, such as tert. Amines, - initially with suitable acid chlorides, such as POl ₅ , POO! «, PGl ,, SO ₂ Cl ₂ , SOCl ₂ , methanesulphonic acid chloride, cyclohexanesulphonic acid chloride, decanesulphonic acid chloride, benzenesulphonic acid chloride, p-ioluenesulphonic acid chloride, phosgene, chloroformic acid ethyl ester, oxalic acid chloride, oxalic acid chloride then the reaction mixture with a suitable amino compound according to the method of the invention for reaction.

Suitable inert solvents in which the reaction according to the invention can be carried out are, for example: Hydrocarbons such as petroleum ether, ligroin, cyclohexane, benzene, toluene and xylene; Chlorinated hydrocarbons, such as Methylene chloride, chloroform, carbon tetrachloride, ethylene = 'chloride, trichlorethylene, chlorobenzene, dichlorobenzene, Trichlorobenzene and chloronaphthalene; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, anisole, diphenyl = ether; and esters, such as ethyl acetate, butyl acetic acid =

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ester, methyl glycol acetate, methyl benzoate. In such Cases in which the active lactam derivatives are not produced in situ with the aid of acid chlorides, but as

isolated defined compounds - e.g. B. lactimether or Lactamacetals - also not inert ones can be used Solvents are also used, e.g. B. alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec, -butanol, Hexanol, decanol, glycol, glycerine, ethyl glycol, Diethylene glycol, triethanolamine; Acid amides, such as formamide, Acetamide, N-methylformamide, dimethylformamide, N-methyl = pyrrolidone; Ketones, such as acetone, methyl ethyl ketone, methyl = isobutyl ketone, cyclohexanone, acetophenone; and nitriles, like Acetonitrile, propionitrile, benzonitrile.

For the in situ preparation of the compounds of the formula (III) or (YI), at least 1 hol of acid chloride per mole of lactam, if necessary an excess, for example 0.2 to 0.5 mole, must be used; if necessary, acid-binding agents, for example tert-amines, can also be used.

At least 1 equivalent of amino compounds, but generally an excess of 0.1 to 10 mol, preferably 0.2 to 5 mol, must be used per mole of compounds of the formula (III) or VI). To prepare dimolecular compounds of the formula I, it is expedient to use reactive lactam compound ^N and amino compounds in equimolar amounts.

The reaction on which the process according to the invention is based can also - especially when using the less reactive lactam derivatives, such as lactim ethers, lactam acetals, An = hydrodilactams - by adding certain acidic or basic ones Agents are accelerated; for example by catalytic bia atochiometric amounts of hydrogen halide acids, methanesulfonic acid, dodecanesulfonic acid, Oyclo =

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hexanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, phosphoric acid, phosphonic acids5 by Lewis acids, such as? 2 ° 5 ^> AlCl ₃ , FeCl ₅ , SnCl ₄ , TiCl _{41 SbCl 5} , BF ₃ ; by tert-amines, such as. Triethylamine, triethylenediamine, pyridine, dimethyl = piperazine; by sodium, potassium, NaOCH ₃ , KO-tert-butyl, NaOH, KOH, Ca (OH) ₂ , CaO and BaO.

The reaction temperature is generally between -2O ⁰ C and 300 ⁰ C, preferably between O ⁰ C and 200 ⁰ C.

In the cases where the "reactive lactam compound" is prepared of the formula (III) or (VI) in situ from a lactam and an appropriate acid chloride, the procedure is useful with afcufenweiser temperature profile: First, at temperatures of -2O ⁰ G to 5O ⁰ C, then at temperatures from -20 ° to 300 ⁰ O, preferably 50 to 20O ⁰ O.

A suitable embodiment of the process according to the invention consists, for example, in that the "reactive lactam compound ¹¹ - optionally dissolved or suspended in a suitable solvent - is added to the optionally dissolved or suspended amino compounds at reaction temperature, optionally the accelerating agents mentioned on page 12 are added and then In cases in which, for example, lactim ethers, lactim thioethers, lactam eetals, lactam captals or anhydrodila gtams are used as reactive lactam compounds, components which split off in the course of the reaction, such as alcohols, phenols, mercaptans, thiophenols or lactams, can optionally be distilled from the Reaction mixture are removed.

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In another suitable variant of the process according to the invention, the lactam is brought - if appropriate in one inert solvent dissolved or suspended - with a suitable acid chloride at reaction temperature for reaction, then carries the amino compound according to the invention - optionally dissolved or suspended in a suitable solvent - In the reaction mixture of the reactive lactam compound prepared in situ in this way, or vice versa the "reactive lactam compound" to the amino compound and brings the reaction mixture gradually to a higher reaction temperature until the reaction and rearrangement according to the above Pormel images are complete.

The products of the process are worked up, if necessary after stripping - if appropriate under reduced pressure - of solvents and excess amino compound by distillation - if appropriate under reduced pressure and (or) recrystallization.

In those cases where - z. B. in the "in situ" process (mineral) acid salts of the process products, the reaction mixture is expediently before further work-up - using suitable water immiscible or only limited miscible solvents - with aqueous alkalis, such as NaOH, KOH, Ca (OH) ₂ , Ba (OH) ₂ , NaHCO ₃ , Na ₃ CO ₅ , K ₉ CO ,, extracted.

The products of the process represent valuable intermediate products for the manufacture of pharmaceuticals (for example after the German patent specification 1 131 688), as well as plastics, \ coatings, resins, pesticides and auxiliaries, for example vulcanization accelerators (according to Russian patent specification 112 941), or are themselves as Pharmaca to be used, for example according to British patent specification 1,023,792 or according to the Australian patent 266 847.

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Example 1 **

In a solution of 60 g phosgene in 250 ml of toluene is allowed to run with stirring, the solution of 56.5 g (0.5 mole) of caprolactam in 150 ml toluene over 1 hour at -10 ^0C. The temperature is now allowed to rise to 20 ^° C. and excess phosgene, together with part of the solvent, is then drawn off into a well-cooled receiver in a water-jet vacuum. The surviving crystal is now entered into a finely divided slurry of 108 g (1 mol) of o-phenylenediamine in 1000 ml of o-dichlorobenzene at room temperature with good stirring, the reaction mixture by passing dry nitrogen heated while toluene up to a bottom temperature of 180 ⁰ C distilled off. The 2-phase mixture is kept for 3 to 4 hours under nitrogen with thorough stirring at 180 ^° C., allowed to cool and stirred into a mixture of 150 g of sodium hydroxide solution and 500 ml of ice water. After thorough mixing, the organic phase is separated off, dried over Na ₂ SO., Concentrated in vacuo and distilled in a high vacuum. After a forerun of excess ο-phenylene diamine = 80 g (78.8 # of theory) of 2- (5'-aminopentyl) -benzimidazole, almost colorless crystalline solidifying oil from kpq _n ~ 207 ⁰ C.

Example 2

A mixture of 104.5 g (0.5 mol) Anhydrodicaprolactam and ⁸¹ g (0.75 mol) of o-phenylenediamine is melted under nitrogen, held for 1 hour with stirring at 8O ⁰ C, then brought in 1 hour to 200 ⁰ C. and held at this temperature for 30 minutes. After cooling to 100 ⁰ C is fractionated in an oil pump vacuum; is obtained after a forerun of caprolactam and excess o-phenylenediamine 66.5 g (76.3 fo of theory) of 2- (5'-aminopentyl) -benz = imidazol a boiling _{n n7} 207 ⁰ C. The compound is identical

UyUf

with that obtained according to Example 1.
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Example 3 ^

18 g of dry HCl are passed into a solution of 32.5 g (0.3 times) of o-phenylenediamine and 28.3 g (0.25 mol) of piperidone O-methyl ether in 400 ml of absolute ethanol, with cooling and stirring at room temperature a. The pink suspension is kept for a further 10 hours with stirring at room temperature, then for 6 hours while nitrogen is passed through at reflux temperature. It is then concentrated to dryness, the remaining salt is taken up in a solution of 50 g of 45% sodium hydroxide solution in 300 ml of water and shaken out 3 times with 100 ml of CH ₂ Cl ₂ each time. The combined organic phases are over Na ₂ SO. dried, concentrated under reduced pressure, the residue that remains was fractionally distilled in a high vacuum. In this way, 35 g is obtained (74 ° i of theory) of the previously undescribed 2- (4'-aminobutyl) -benzimidazole, almost colorless spherulitic solidifying oil from kpq, -206 to 210 ⁰ C.

Example 4

A mixture of 105.6 g (0.5 mol) of laurolactim ethyl ether, ⁸¹ g (0-75 mol) of o-phenylenediamine and 1 g of p-toluenesulfonic acid is melted under nitrogen and ^{heated to 250 °} C. with stirring, 14 g of methanol distilling over . It is held at this temperature for a further 3 hours and the melt is then fractionally distilled in a high vacuum. In this way one obtains 102 g (71 $ of theory) of 2- -benzimidazole (11 ^{-Aminoundecyl!)} - not previously been described as colorless crystals from _{n o} Kp 25O ⁰ C and 8O ⁰ C mp (6 parts Essigester).

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Example 5 ^ O

A solution of 11.3 g (0.1 mol) of A ¹ -2-methoxy-4,4-dimethylazetin in 50 ml of anhydrous ethanol is added at 2O ⁰ G to a solution of 13 g (0.12 mol) o- phenylenediamine in 100 ml ethanol, bringing to reflux under nitrogen, holding for 2 hours at 80 ⁰ C and excess solvent is then distilled largely under atmospheric pressure. 100 ml of o-dichlorobenzene are then added to the reaction mixture and the mixture is heated under nitrogen for a further 4 hours at reflux temperature. After concentration under reduced pressure, 11 g (58 $ of theory) is obtained of 2- (2'-amino-2 ^{f-methyl-propyl)} -benzimidazole, colorless crystals of Pp 21O ⁰ C '(3 parts dimethylformamide).

Example 6 ■

31.8 g (0.25 mol) of caprolactim methyl ether are allowed to run into 31.3 g (0.25 mol) of o-aminothiophenol ^{at 0 ° C. with cooling and stirring;} thereafter the mixture is heated gradually under nitrogen and distilled 8 g of methanol over a bridge up to a bottom temperature of 200 ⁰ C from. Subsequent distillation of the remaining oil in a high vacuum gives 48.5 g (88 56 of theory) of 2- (5'-aminopentyl) benzothiazole, yellowish oil with a boiling point of ₀₀₅ 133 ⁰ C.

Example 7

To a solution of 15 g (0.12 mol) of o-aminothiophenol in 100 ml of methanol, ⁰ C allowed under stirring and cooling at O, the solution of 11.3 g (0.1 mol) of 2-methoxy-4,4- dimethylazetin enter, then brought to reflux under nitrogen and holding for 1 hour at 66 - 70 ⁰ C. After concentration under reduced pressure is an oil pump vacuum fractionally distilled; in this way 17.5 g (85 fi of theory) are obtained

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y as yellowish crystals of bp _{n Λ 104-105} ⁰ C and Pp 54 ⁰ C (cyclohexane). υ, ι

Example 8

A mixture of 15.5 g (0.2 mol) of cysteamine, 25.5 g (0.2 mol) of caprolactim methyl ether and 150 ml of anhydrous ethanol is brought to reflux with stirring and nitrogen bubbling over the course of 2 hours, and a further 2 hours therein 80 ⁰ C held. Subsequently, the solvent is distilled off up to a bottom temperature of 150 ⁰ C at atmospheric pressure, and fractionated the behind residual oil in an oil pump vacuum. The yield of A ² -2- (5'-aminopentyl) -thiazoline is 23.8 g (69 i "of theory), colorless liquid, bp 156 ° C .. c.

Example 9

A solution of 54.7 g (0.5 mol) of o-aminophenol and 63.7 g (0.5 mol) in 200 ml of ethanol provides Caprolactimmethyläther according to Example 8-72 g (70 f 'of theory) of 2- ( 5'-aminopentyl) benzoxazole, a colorless crystalline solidifying oil, bp _{10176 to} 180 ⁰ C or _Q Kp _Q8 125 ° C The compound previously described is stable only briefly after distillation and gradually decomposes under separation.

Example 10

In a solution of 120 g of phosgene in 500 ml of dichlorobenzene is allowed to run the solution of 113 g (1 mole) of caprolactam in 300 ml of dichlorobenzene under stirring and cooling at -10 ⁰ C over 1 1/2 hours. The temperature is now allowed to rise to 20 ^° C. and excess phosgene is drawn off together with part of the solvent in a steam jet vacuum. If we now again cooled to -10 ⁰ C, is all at once the slurry

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of 164 g (1.5 mol) of ο-aminophenol in 500 ml of dichlorobenzene with thorough stirring, then gradually heated to 180 ^° C. under nitrogen over the course of 3 hours, with a clear solution after initial oiling. Subsequently, the solvent at atmospheric pressure is distilled off up to a bottom temperature of 26O ⁰ C, which behind residual oil is stirred into a mixture of 300 g of 45 $ aqueous sodium hydroxide solution and 500 g of ice and receives the oil which separates into a total of 1 liter of methylene chloride. The combined organic phases are on NapSO. dried, concentrated under reduced pressure, the remaining oil is distilled in vacuo. Obtained in this way 125 g (61 fi of theory) of 2- (5 '-Aminopentyl) -benzoxazole, bp, _Q 176 -. 18O ⁰ C. The compound is identical with the compound obtained according to Example 9 substance.

Example 11

1 g of p-toluenesulfonic acid is added to the solution of 75 g (1 mol) of 1-aminopropanol-2 and 63.6 g (1/2 mol) of caprolactia methyl ether in 400 ml of anhydrous ethanol, and it is kept at room temperature for 5 hours while stirring, thereafter bringing the reaction mixture to reflux and holding sum 3 - 4 h at 80 ⁰ C. After cooling, the solvent is removed under reduced pressure, the residue is taken up in 400 ml methylene chloride and shaken with 20 ml 20% sodium hydroxide from. After drying over Na ₂ SO. the mixture is concentrated under reduced pressure and, with fractional distillation of the remaining oil, 57 g (67 $> d.! Dh.) of Δ -2- (£ -aminopentyl-5-methyl-oxazoline as a colorless oil with a _{boiling point of Ί} 78 - 81 ⁰ O.

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Example 12

A solution of 106 g (0.5 mol) Laurinlactimmethyläther, 46 g (0.75 mol) of aminoethanol and 1.5 g of p-toluenesulfonic acid in 500 ml of anhydrous ethanol is kept for 1 day at 2O ⁰ C, then 8 hours at reflux temperature. The solvent is then distilled off first under normal pressure and later under reduced pressure, the remaining oil is taken up in 500 ml of CH ₂ Cl ₂ , extracted with 200 ml of 5% sodium hydroxide solution, the organic phase is dried over Na ₂ SO ₄ and concentrated reduced pressure. In the subsequent fractional distillation in an oil pump vacuum resulting 72 g (60 <fo of theory) of Δ -2- (11 • -Aminoundecyl) -oxazoline, • a colorless, solidifying to a crystalline mass oil, bp _{0 05} 128 - 13O ⁰ C and EP 70 ⁰ C.

Example 13

In a solution of 65 g phosgene in 500 ml of o-dichlorobenzene is allowed with good stirring and cooling at -10 ⁰ C, the solution of 63.6 g (0.5 mol) of N-Methylcaprolactarn in 400 ml of o-dichlorobenzene to run, wherein a dense crystal pulp is created. The temperature is allowed to rise to 30 ^° C. and excess phosgene, together with part of the solvent, is drawn off over a bridge with a well-cooled receiver in a steam-jet vacuum. A slurry of 81 g (0.75 mol) of o-phenylenediamine in 300 ml of o-dichlorobenzene is then stirred into the crystal slurry, then heated to 150 ^° C. over the course of 1 hour while passing nitrogen through, with oiling to form a 2-phase mixture. Now bringing the temperature with stirring to 180 ⁰ C, holding for 3 hours at reflux, allowed to cool with stirring, the crystals separated out thereby is filtered off and stirred in it into a mixture of 200 g of 45 #iger sodium hydroxide solution and 400 g of ice water. The mixture is shaken several times

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with a total of 1 liter of methylene chloride, the organic phase is dried over NapSO and concentrated under reduced pressure. In distillation of the remaining residue on behind the oil pump (57 of theory i °) was obtained 52.5 g of 2- (5'-methyl = aminopentyl) -benzimidazole, spherulitic solidifying oil, ^bp 0.1 ^195-2 OO ⁰ C.

Example 14

The solution of 29 g (0.2 mol) of N-methylpyrrolidone dimethylacetal in 50 ml is added to the solution of 31.2 g (0.25 mol) of o-aminothiophenol in 100 ml of o-dichlorobenzene with stirring at ^{0 ° C.} o-dichlorobenzene run in, then the reaction mixture heated under nitrogen up to a bottom temperature yon 18O ⁰ C, whereby 12 g of methanol are distilled off over a bridge; then it is held at reflux temperature for a further 2 hours, solvent is drawn off in vacuo and the oil which remains is fractionated in a high vacuum. The .2- (3-methylaminopropyl) benzothiazole boiling ₂ ¹¹ 5 at Kp _Q - 117 ⁰ C, almost colorless oil. The yield is 30 g (73% of theory).

Example 15

35 g of phosgene are introduced into a solution of 4-0 g (0.25 mol) of N-phenylpyrrolidone in 500 ml of o-dichlorobenzene with stirring at ⁰ ° C., then brought to 30 ^° C. and kept at this temperature for 3 hours. Excess phosgene and part of the solvent are then drawn off in a steam jet vacuum, a suspension of 45.5 g (0.375 mol) of 4-methyl-1,2-di = aminobenzene in 300 ml of o-dichlorobenzene is then introduced into the reaction mixture while stirring and passing nitrogen over to reflux, an oily two-phase mixture. After 5 hours, 180 ⁰ C is allowed to cool and works, the reaction mixture by vigorous shaking with a mixture of 100 g sodium hydroxide 45 #iger

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and 300 ml of water. After drying over Na ₂ SO and concentration, the organic phase yields a viscous oil which is fractionally distilled in a high vacuum. 35 g (52.8 <fo of theory) of 2- (3'-phenylaminopropyl) -5-methylbenzimidazole are obtained as a brownish, non-crystallizing resin with a boiling point of _{0 05} 240 ⁰ O.

Example 16

In a solution of 23 g (0.375 mol) of 2-aminoethanol in 100 ml of ethanol is allowed under cooling and stirring at 0 - 10 ⁰ G, the solution of 43.3 g (0.25 mol) of N-methyl-dimethylacetal in 100 ml ethanol arrive, then brought to reflux and maintaining the reaction mixture for 2 hours at 80-83 ⁰ C. Thereafter, the solvent is distilled up to a bottom temperature of 200 ⁰ C, and obtained in the fractional distillation dee residue under reduced pressure, 39 g (91.5 i ° of theory) of Δ -2- (ω-Methylaminopentyl) -oxazoline, colorless oil, ^bp 0.4 ⁸⁵ ~ ⁹⁰ ° ^C ·

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Claims (9)

Patent claims: iP. Process for the production of five- or six-membered
Heterocycles of the general formula I, in which A is a bivalent, unsubstituted or substituted,
aliphatic, cycloaliphatic ^ araliphatic or aromatic radical, XO, S or, if A is not an aliphatic radical, NR,
R and R are hydrogen, halogen, nitro, aliphatic ^, cycloaliphatic, araliphatic ^ and / or aromatic radicals which are both identical and different
can, and which are linked to one another in a ring can,
ρ R is hydrogen, an aliphatic, cycloaliphatic ^ araliphatic or an aromatic radical and η represents an integer from 2-15, where the carbon chain defined as - {0} "- if heteroatoms and / or substituted or unsubstituted bivalent hetarylene or / and arylene radicals and / or double or / and triple bonds, or of dimolecular compounds of the formula I, the linkage being via 1 2
A, R, R, R or via the coals defined in the above substance chain - 0 L- containing aromatic or unsaturated radicals can take place, the respective link being included only once in the formula, characterized in that compounds of the formula 1 \ NH ₂ ¹¹ ^ XH Le A 13 569 - 24 - 20984A / 1188 in which A and X have the abovementioned meaning or, as defined above, dimolecular compounds of the formula II with cyclic ImiÄen of the formula III, III wherein R and R have the abovementioned meaning and ΐ is a nucleofugic leaving group, or as defined above dimolecular compounds of the formula III or with cyclic amide compounds of the formula VI ^yi 1 2
wherein R, R and R have the meanings given above, Z = Y when Y is halogen, -OR ⁵ or -SR ⁵ , and Z is OPCl ₄ , OPOCl ₂ , OPCl ₂ , OSO ₂ Cl, OSO ₂ R ⁵ , -0-C0C1 or OCOR ⁵ when Y is halogen, wherein R represents an alkyl or aryl group, or with dimolekularen as defined above compounds of formula VI, optionally dissolved in the melt of the components or or suspended in solvents at temperatures between -20 ⁰ C and 300 ⁰ C converts. 2. Process for the preparation of the heterocycles of the general formula I, in which the radicals A, R, R and R are replaced by halogen, Cyano, nitro, amino, hydroxy, ether, thioether, ester, or / and sulfonyl groups are identical or differently substituted are, according to claim 1. 3. The method according to claim 1, characterized in that the compounds of formula III lactim alkyl ethers, lactim aryl ethers, Lactim alkylthioether or lactimarylthioether is used. Le A 13 569 - 25 - 2098U / 1183 4. The method according to claim 1, characterized in that the compounds of formula II Dilactimäther R ^1> used. 5. The method according to claim 1, characterized in that one as compounds of the formula II anhydrodilactams O R used. 6. The method according to claim 1, characterized in that one as compounds of the formula II lactim chloride or lactim chloride hydrochloride R ^ s ■ w ρ ^ * -— w · um X JM Λ s - Xl XlOX used. 7. The method according to claim 1, characterized in that the compounds of the formula VI lactamacetals, lactammercaptals or lactam chlorides "I ^{X (C)} n C ^{X (C)} " * R ⁿ <C-SR ³ R ^V , ^xl used. Le A 13 569 - 26 - 20984A / 1188 8. The method according to claim 1, characterized in that the compounds of formula (III) or (VI) "in situ" from N-unsubstituted or N-eubstituted lactams with acid chlorides, in particular with POl ₅ , POl ₅ , POl, , SO ₂ Cl ₂ , SOOl ₂ , alkane sulfonic acid chlorides, arylsulfonic acid chlorides, phosgene, chloroformic acid esters, oxalic acid methylester chloride, oxalic acid dichloride, toluic acid chloride and / or trifluoroacetic acid chloride. 9. Compounds of the formula I. NO Λ «2 wherein A, R, R, R and η have the meaning given above and X = O. Le A 13 569 I 209844/1188