WO1982002046A1 - Method of preparation of delta2 n-heterocycles - Google Patents

Abstract

Method of preparation of $g(D)?2 N-heterocycles having the general formula I$(10,)$wherein v is an integer from 1 to 4, R1? represents (if v=1) hydrogen, one of the following residues: alkyl with 1 to 19 carbon atoms, aralkyl with 7 to 10 carbon atoms or cycloalkyl with 5 to 7 carbon atoms, these residues being optionally substituted by hydroxy, amino, nitro, fluorine, chlorine, bromine, C1?-C4? alkoxycarbonyl, di-C1?-C4? alkylaminocarbonyl, C1?-C4? alkylaminocarbonyl, tri-C1?-C4? alkylsilyloxy-, tetrahydropyranyloxy or benzyloxy; or one of the oxo-alkyl with 1 to 6 carbon atoms, aryl residues or an heterocycle having 5 to 6 links with 1 to 3 nitrogen, oxygen or sulphur atoms as heteroatoms; R1? represents (if v=2) an arylene residue, an alkylene -(CH2?)-m? residue, wherein m is 1 to 6, and which may be substituted by hydroxy, oxo, amino, nitro, fluorine, chlorine, bromine, tri-C1?-C4? alkylsilyloxy, or benzyloxy; or the -CH=CH- residue; R1? represents (if v=3 or 4) a benzene residue with 3 to 4 free valences or an alkylene -(CH2?)-m? residue with 3 to 4 free valences, which may optionally be substituted by hydroxy, oxo, amino, nitro, fluorine, chlorine, bromine, tri-C1?-C4? alkylsilyloxy, tetrahydropyranyloxy, or benzyloxy; D represents an imino residue or a direct link; Y represents an oxygen or sulphur atom, or an imino residue or N-(C1?-C4? alkyl)-imino; Z represent the (CR6?R7?)n? residue wherein n may be 0 to 3; R2? represents a hydrogen atom, an alkyl residue with 1 to 6 carbon atoms, optionally substituted by hydroxy or amino; or a C1?-C4? alkoxycarbonyl, cyano or di-C1?-C4? alkylaminocarbonyl residue; R3?, R4?, R5?, R6?, R7? each represent a hydrogen atom, an alkyl residue with 1 to 6 carbon atoms, optionally substituted by hydroxy or amino; or an aryl residue; R3? and R4? represent together a trimethylene, tetramethylene or 1,3-butadienylene residue, to the extent that R2? and R5? represente together a direct link; this method utilizing as starting compounds those having the general formula$(6,)$wherein R1?, D and v have the above-mentioned meanings, and X represent an oxygen or sulphur atom or the residue$(5,)$R8? represents hydroxy, a C1?-C6? alkoxy residue, a C1?-C6? alkylthio residue, an aryloxy or arylthio residue, an aralkyloxy or aralkylthio residue with 7 to 10 carbon atoms, a C1?-C4? trialkylsilyloxy or C1?-C4? trialkylaralkylsilythio residue; this method utilizing as starting compounds also the amines of general formula$(6,)$wherein R2?, R3?, R4?, R5?, Y and Z have the above-mentioned meanings; that method is characterized by the fact that the reaction is carried out by means of organic phosphines or of phosphonium salts and perhalogenated hydrocarbons or ketones respectively with azodicarboxylic acid diesters in the presence of tertiary amines.

Description

METHOD FOR PRODUCING Δ ² N-HETEROCYCLEN

The invention relates to a new process for the preparation of Δ ² -N heterocycles.

The process products are suitable as intermediates for the production of active pharmaceutical ingredients, but also have biological activity themselves, such as, for example, as diuretics. The process serves in particular to introduce Δ ² -Gxazolin-, Δ ² -Thiazolin and Δ ² -Imidazolin protective groups in carboxylic acids.

Δ ² -N-heterocycles, such as, for example, Δ ² -oxazolines, Δ ₂ -thiazolines or Δ ² -imidazolines, can only be started under very drastic conditions starting from the carboxylic acids or their derivatives and corresponding amines such as ethanolamine, cysteamine and 1,2-ethylenediamine by heating the components to 70-250 ° C [AIMeyers et al., Angew. Chemistry, 88: 321 (1976); RC Elderfield, Heterocyclic

Compounds Vol. V, 679; Chem. Rev. 54, 593 (1954)]. According to another method of presentation, corresponding N-acyl derivatives are cyclized with SOCl ₂ , tosyl chloride / pyridine, H ₂ SO ₄ , P ₂ O ₅ or P ₂ S ₅ [JAFrump, Chem. Rev. 71, 483 (1971)].

All of these methods either require high temperatures, such as heating to 70-250 ° C, or involve multiple steps, or use aggressive reagents to cyclize the amides in question. (H ₂ SO ₄ , SOCl ₂ , P ₂ O ₅ or P ₂ S ₅ ). A transfer of sensitive carboxylic acids, esters or amides, as they are usually found in natural products, into the corresponding Δ ² -oxazolines,

Δ ² -thiazolines, Δ ² -imidazolines or their higher-linked analogues are therefore very difficult or often not possible. It has now been found that the Δ ² -N-heterocycles mentioned can be prepared under particularly mild conditions and directly from carboxylic acids or a carboxylic acid derivative by reaction with a suitable amine in a technically useful manner if the reaction with organic phosphines or organic phosphonium salts and perhalogenated hydrocarbons or ketones or with azodicarboxylic acid ediest ern in the presence of tertiary amines.

The imirie or thioamides II (e.g. N-ß-hydroxyethyl-phenylacetic acid amiü), which can be isolated as intermediates or produced in other known ways, can also be used with phosphines and perhalogenated hydrocarbons or with

Azodicarboxylic acid diesters in the presence of tertiary amines to αen desired Δ ² -N heterocycles who converted the. The present process also offers the advantage of achieving high yields of Δ ² -N-etching even without isolating the intermediates.

The invention thus relates to a process for the preparation of Δ ² -N-heterocycles of the general formula I.

in der v 1 bis 4 R₁ (für v=1) Wasserstoff, die gegebenenfalls durch Hydroxy,

in which v 1 to 4 R ₁ (for v = 1) are hydrogen which may be replaced by hydroxy,

Amino, nitro, fluorine, chlorine, bromine, C ₁ -C ₄ -alkoxycarbonyl, DiC ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkylaminocarbonyl, tri-C ₁ - C ₄ -alkylsilyloxy-, tetrahydropyranyloxy or benzoyloxy-substituted radicals Alkyl with 1-19 carbon atoms, aralkyl with 7-10 carbon atoms or Cvcloalkyl with 5-7 carbon atoms, an oxoalkyl radical with 1-6 carbon atoms, an aryl radical or a 5- or 6-membered heterocycle 1-3 N, O or S heteroatoms,

R ₁ (for v = 2) is an arylene radical, optionally by hydroxy,

Oxo, amino, nitro, fluorine, chlorine, bromine, tri-C ₁ -C ₄ -alkylsilyloxy, benzoyloxy-substituted alkylene - (CH ₂ ) - _m , where m can be 1 to 6, or the rest -CH = CH-,

R ₁ (for v = 3 or 4) is a 3- or 4-membered berzol residue or optionally by hydroxy, oxo, amino, nitro, fluorine,

Chlorine, bromine, tri-C ₁ -C ₄ -alkylsilyloxy, tetrahydropyranyloxy,

Benzoyloxy substituted trihydric or tetravalent alkylene

- (CE ₂ ) - _m where m can be 1 to 6,

D an imino residue or a direct bond,

Y oxygen, sulfur, imino or N- (C ₁ -C ₄ alkyl) imino,

Z the remainder (CR ₆ R ₇ ) _n where n can be O to 3,

R _{2 is} hydrogen, optionally substituted by a hydroxy or amino group, alkyl having 1-6 C atoms, C ₁ -C ₄ alkoxycarbonyl, cyano or di-C ₁ -C ₄ alkylaminocarbonyl,

0 "P1 R ₃ , R ₄ , R ₅ , R ₆ , R _{7 are} hydrogen, alkyl which is optionally substituted by a hydroxyl or amino group and has 1-6 C atoms or aryl,

R ₃ and R ₄ together trimethylene, tetramethylene or 1, 3-butadienylene if R ₂ and R ₅ together represent a direct bond.

from compounds of the general formula II

worin R₁, D und v die oben angegebenen Bedeutungen haben,II,

wherein R ₁ , D and v have the meanings given above,

an oxygen or sulfur atom or the rest and

R ₈ is hydroxy, C _1- C ₆ alkoxy, C ₁ -C ₆ alkylthio, aryloxy or -thiorest, a Aralkyioxy- or -thiorest with 7-10 C atoms, a C ₁ -C ₄ - Represent trialkylsilyloxy or thio radical or a tri-C ₇ -C ₁₀ aralkylsilylexy or thio radical, and amines of the general formula III

wherein R ₂ , R ₃ , R ₄ , R ₅ , Y and Z have the meaning given above, characterized in that with the aid of organic phosphines or phosphonium salts and perhalogenated carbon. Hydrogens or ketones or with the aid of azodicarboxylic acid diesters in the presence of tertiary amines. With R ₁ in the meaning of an alkyl group with 1-19 C atoms are straight-chain and branched saturated hydrocarbon radicals with 1-19 C atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert. -Butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, in particular those with 1-6 C atoms, which are optionally denoted by hydroxy, amino, nitro, fluorine, chlorine, bromine, C ₁ -C ₄ Alkoxycarbonyl, di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkylaminocarbonyl, tri-C ₁ -C ₄ -alkylsilyloxy-, tetrahydropyranyloxy or benzoyloxy, preferably can be substituted by hydroxy, amino or chlorine if R ₂ , R ₃ , R ₄ ,

R ₅ , R ₆ , R ₇ and R _{8 represent} an alkyl radical with 1-6 C atoms, this is to be understood as radicals as already mentioned for R ₁ . Preferred alkyl radicals for R ₂ to R ₇ and R ₈ are those with 1-4 C atoms. These alkyl radicals can also be substituted, preferably by hydroxy or amino.

For Y with the meaning N-alkyl, alkyl radicals with 1-4 C atoms come into consideration, as have already been mentioned for R ₁ . Aralkyl radicals R ₁ , R ₂ , R ₃ , R ₃ , R ₅ , R ₆ , R ₇ and R ₈ are to be understood as straight-chain and branched radicals with 7-14 C atoms, such as, for example, benzyl, 1-phenylethyl, 2- Phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, α-naphthylaethyl, ß-Na-phthylmethyl, 1- (α-naphthyl) ethyl, 2- (ß-naphthyl) ethyl, 4- (ß-Naphthyl) -butyl, etc. Are preferred radicals with phenyl in the meaning of Ar with 7-10 C atoms, which may be replaced by hydroxy, amino, nitro, fluorine, chlorine, bromine, C ₁ -C ₄ alkoxycarbonyl, Di -C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkylaminocarbonyl, tri-C ₁ -C ₄ -alkylsilyloxy-, tetrahydropyranyloxy or benzoyloxy, preferably can be substituted by hydroxy, amino or chlorine.

Phenyl, α- and β-naphthyl, preferably phenyl, are suitable for the radicals R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ as aryl.

For R ₂ in the meaning of alkoxycarbonyl. the following alkyl radicals for alk come into consideration: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert. -Butyl and benzyl. Dialkylaminocarbonyl in the meaning of R ₂ should be a radical in which alkyl is a straight-chain saturated alkyl radical with 1-4 C atoms (methyl, ethyl, propyl, butyl).

In - (CR ₆ R ₇ ) - as a possibility of Z, n can have the size 0 to 3. Compounds with n = 0 or 1 are preferred.

If R _{1 represents} a cycloalkyl radical with 5-7 C atoms, this means radicals such as cyclopentyl, cyclohexyl, cycloheptyl, ethylcyclohexyl, ethylcyclopentyl, methylcyclohexyl, which are optionally substituted by hydroxy, amino, nitro, fluorine, chlorine, bromine, C _1- C ₄ -alkoxycarbonyl, di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkylaminocarbonyl, tri-C ₁ -C ₄ -alkylsilyloxy-, tetrahydropyranyloxy or benzoyloxy, preferably substituted by hydroxyl, amino or chlorine. Suitable 5- or 6-membered heterocycles with 1-3 N, O or S heteroatoms are: pyrryl, thienyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, cxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, pyrimidyl, pyrazinyl, pyridazinyl , Azepinyl etc.

In R ₁ (for v = 2), arylene means the residues o-, m- or p-phenylene and all possibilities which exist for the naphthylene residue. Preferred residues are the phenylene residues.

The optionally by hydroxy, oxo, amino, nitro, fluorine, chlorine,

Bromine, tri-C ₁ -C ₄ -alkylsilyloxy, tetrahydropyranyloxy, benzoyloxy, preferably substituted by hydroxyl, amino or chlorine - (CH ₂ ) _m radicals in R ₁ can be straight-chain or branched-chain alkylene radicals such as, for example, methylene, ethylene, trimethylene, tetramethylene , Pentamethylene, hexamethylene, methyltrimethylene, ethylethylene, ethyltetraaethylene, etc., where m is 1 to 6. The residues with m = 1-4 should preferably be.

The radicals C _1- C ₆ alkoxy, C _1- C ₆ alkylthio, aryloxy, arylthio, aralkylthio, aralkyioxy, C _1- C ₄ -trialkylsilyloxy- or -thio or triaralkylsilyloxy- or -thio each correspond to those already for R ₁ mentioned residues alkyl, aryl, aralkyl. The starting materials II, especially organic carboxylic acids such as acetic acid, adipic acid, fumaric acid, benzoic acid, terephthalic acid, trimesic acid, citric acid, phenylacetic acid, 2-phenyl propionic acid (hydratropic acid), pyruvic acid, mesoxalic acid, nicotinic acid, isonicotinic acid, naphthoic acid, cyclohexanecarboxylic acid, furancarboxylic acid, thiophenecarboxylic acid and come the already defined esters of these acids.

Preferred amines III for the cyclization to Δ ² -N-heterocycles in the 5-ring series are ethanolamine, 2-aminopropanol, 2-methyl-2-aminopropanol, tris (hydroxymethyl) methylamine, o-aminophenol,

Cysteamine, 1,2-ethylenediamine, o-phenylenediamine, 1-amino-2-methylaminoethane, 1-amino-2-phenylamino- or 2-benzylaminoethane, and in the 6-ring series 3-aminopropanol, 2,3, 3-trimethyl-3-amino-1-propanol, 3-aminopropanethiol, 1,3-diaminopropane or 1,3-diamino¬

namentlich genannt worden sind^, n bestimmt die Ringgröße derpropane the formula as far as not yet

have been named ^, n determines the ring size of the

Δ ² heterocycles of the general formula I. For example,

for n = 0 Δ ² -oxazolines, Δ ² -thiazolines and Δ ² -imidazolines, for n = 1 5, 6-dihydro-4H-1, 3-oxasine, 5, 6-dihydro - 4H-1, 3- thiazines and tetrahydro-pyrimidines and for n = 2 and 3 the corresponding 7- or 8-membered rings.

Suitable organic phosphines or phosphonium salts are R ₉

Aryl (phenyl, α- or β-naphthyl, preferably phenyl), aralkyl

(with 7-10 carbon atoms as stated above), alkyl (with 1-6

C atoms, see radicals for R ₁ ), cycloalkyl (with 3-7 C atoms, see

Radical e for R ₁ ), O-aryl (phenyl, α- or β-naphthyl, preferably

Phenyl), 0-alkyl (with 1-6 C atoms, see radical e for R.) and DiC _1- C ₄ alkyl) -amino (preferably dimethylamino) or as

Da die Reaktionsgeschwindigkeit in der oben beschriebenen Heihenf l b i t i t (R₉) P fü R A l u w ise Ph nyl am

Since the reaction rate in the Heihenf lbitit (R ₉ ) P für RA luw ise Ph nyl am

nhine, in denen Triarylphosphine an eine polymere r e s gebunden sind, bevorzugte Reagenzien.

Also, in which triarylphosphines are bound to a polymeric res, preferred reagents.

Perhalogenated aliphatics and aralkyls and carbonyl compounds such as CCl ₄ , CBrCl ₃ , CBr ₂ Cl ₂ , CClBr ₃ , CBr ₄ , C ₂ Cl ₆ , C ₆ H ₅ -CCl ₃ , CCl ₃ -CO-CCl ₃ CCl are used as electrophilic components ₃ is -CH _3, CHBr _3, CCl ₃ CN, CCl _3, etc. but preferably -CHO CCl ₄ and C ₂ C _16,

vorzugsweise mit R₁₁=CH₃, C₂H₅ as azo ester R ₁₁ OOC-N = N-COOR ₁₁ with R ₁₁ = CH ₃ , C ₂ H ₅ ,, CH ^ Cl,

preferably with R ₁₁ = CH ₃ , C ₂ H ₅

amin, Tributylamin, Diisopropyläthylamin, Dicyclohexyläthylamin, Benzyldimethylaain, Pyridin, Lutidin, Collidin, 2-Dimethylaminopyridin, 4-Diaethylaminopyridin, Chinolin, 1,4-Diazobicyclo [4,3,0]non-5-en (DBN), 1,8-Diazobicyclo[5,4,0]undec-7-en (DBU) 1,4-Diazabicyclo[2.2.2]octan (DABCO), vorzugsweise Triäthylamin und Pyridin verwendet.As tert.Aeine in, triethylamine, tri-n-propyϊ

amine, tributylamine, diisopropylethylamine, dicyclohexylethylamine, benzyldimethylaain, pyridine, lutidine, collidine, 2-dimethylaminopyridine, 4-diaethylaminopyridine, quinoline, 1,4-diazobicyclo [4,3,0] non-5-ene (DBN), 1.8 -Diazobicyclo [5,4,0] undec-7-ene (DBU) 1,4-diazabicyclo [2.2.2] octane (DABCO), preferably triethylamine and pyridine.

The reaction is carried out in non-protic absolute solvents or solvent mixtures such as CCl ₄ , chloroform, methylene chloride, benzene, toluene, ethyl ether, tetrahydrofuran, ethyl acetate, acetonitrile, dimethylformamide (DMF) or sulfolane, preferably in acetonitrile, pyridine or DMF.

The reaction proceeds at temperatures between -20 ° C and 100 ° C, preferably at + 10 ° C to + 30 ° C. It is advantageous to use equivalent amounts of the amine component (ω-hydroxy- and ω-mercaptoamine and

(^ -Diamine) to use. If one starts from the amides or thioamides II, the addition of the amino component III in molar amounts is of course not necessary. The tert. Phosphine (preferably triphenylphosphine) and the electrophile (preferably CCl ₄ or C ₂ Cl ₆ ) are used in a 2-5-fold molar excess, preferably in a 3-4-fold molar excess, based on the carboxyl group. How do you need at least phosphonium salts

2 - 3 equivalents.

From the tert. Amine (preferably triethylamine) is also advantageously used in 2-3 equivalents, preferably at least 4 equivalents. An excess of the triethylamine causes a better solubility of the amine salts of the carboxylic acids.

If one starts from the corresponding amides of ω-hydroxyanine, ω-mercaptoamine or the thioamide of ω-hydroxyamine or finally the monoamide of ω-diamine, only half of the reagents specified above are required for the cyclization.

mäßig, das Triphenylphosphin in Lösung (vorzugsweise in Acetonitril) langsam zu dem Gemisch der anderen Reaktionspartner zuzutropfen, um hohe Ausbeuten der gewünschten Δ²-N-Heterocyclen I zu erreichen.Since the reaction of trisubstituted phosphines (R ₁₁ ) _{3 P} (preferably triphenylphosphine.) With halogen compounds, preferably CCl ₄ , takes place over a whole series of reaction products [cf. R.Appel, Angew. Chem. 87 863 (1975)] and the first reaction products, for example for the cyclizations, it is appropriate

moderate, slowly add the triphenylphosphine in solution (preferably in acetonitrile) to the mixture of the other reactants in order to achieve high yields of the desired Δ ² -N-heterocycles I.

Although all of the products described have high thermal stability and in particular also usually survive treatment with strong bases well - 4,4-dimathyloxazolines are known to be used as protective groups for carboxyl groups - behave in this way some process products in the chromatographic purification on columns with the various adsorbents such as silica gel, aluminum oxide, Florisil, Celite or diatomaceous earth are surprisingly unstable, amides being formed when the ring is opened.

These compounds can be used on very deactivated adsorbents such as e.g. Chromatograph aluminum oxide (A IV-V) or silica gel to which 30-40% water has been added, if possible using pressure, without large amounts of these substances being decomposed during the chromatography.

MJ Miller et al. describe in JACS 198O, 7026 the cyclization of β-hydroxyhydroxamates with triphenylphosphine / diethyl azodicarboxylate. As a by-product, they receive oxazolines in 10-20% yield. It was therefore very surprising that the amides II (z.3. N-β-hydroxyethyl-phenylacetic acid amide) form 60-70% oxazolines under these cyclization conditions. It was also not foreseeable that the single-stage process starting from the carboxylic acid derivatives or carboxylic acids II and de amines III would yield far better yields of Δ ² -N-heterocycles than the multi-stage process by MJ Miller.

Example 1

2-phenyl- Δ ² oxazoline

a) To 2.44 g (0.02 mol) of benzoic acid, 1.2 ml (0.02 mol) of β-hydroxyethylamine, 8.4 ml (0.06 mol) of triethylamine and 4.3 ml (0.045 mol) of carbon tetrachloride in 100 ml abs. Acetonitrile 15 74 g (0.06 mol) triphenylphosphine in 200 ml abs at 23 C with stirring. Acetonitrile was slowly added dropwise while stirring, the temperature rising to 27 °. After stirring for a further 18 hours at 23 ° C, the mixture was filtered, the salts filtered off were washed with 30 ml of acetonitrile and the filtrate was evaporated. After the residue had been dissolved in methylene chloride and washed with 2 N sodium hydroxide solution, the mixture was dried (Na ₂ SO ₄ ) and evaporated. The residue was dissolved in 60 ml of toluene and diluted with 80 ml of hexane, triphenylphosphine oxide precipitating out and being filtered off. The filtrate was distilled at 100-120 ° C at 0.5 mbar in a kettle tube and 2.11 g (71.7%) of pure 2-phenyl-Δ ² -oxazoline was obtained.

b) In an analogous approach with 1,8-diaza-bicyclo [5.4.0] undec-7-ene (DBU) instead of triethylamine, a mixture of 2-phenyl-oxaaolin and DBU was obtained in good yield when extracted with hexane but could not be separated by distillation.

When comparing thin layers in the toluene-ethyl acetate system (1: 1), the 2-phenyl-Δ ² -oxazoline had the same R _F value = 0.45 as an authentic comparison sample.

c) To 2.44 g (0.02 mol) of benzoic acid, 1.2 ml (0.02 mol) of β-hydroxyethylasine, 15.74 g (0.06 mol) of triphenylphosphine and 16.7 ml (120 mmol) of triethylamine in 60 ml abs. N, N-Dimethylformamide (DMF) suspended, 3.8 ml (40 mmol) carbon tetrachloride were added with stirring at 0 ° C and stirred for 1 h at + 3 ° C, 18 h at 24 ° C. Then it was cooled again to 0 ° C and a further 1.9 ml (20 mmol) of CCl _{4 was} added and the mixture was stirred overnight. After filtration and washing with 25 ml of DMF, 200 ml of 2N NaOH were added and extracted with 6 × 120 ml of CH ₂ Cl ₂ . After drying (Na ₂ SO ₄ ) and evaporation, the residue was distilled in a bulb tube and 1.28 g (43.5%) of pure 2-phenyl-Δ ² -oxazoline were obtained.

d) To a mixture of 2.44 g (0.02 mol) of benzoic acid, 1.2 ml (0.02 mol) of β-hydroxyethylamine and 16.7 ml (0.12 mol) of triethylamine in 80 ml of abs. Acetonitrile was a suspension of 40 mmol freshly prepared triphenylphosphine dibromide in 110 ml abs. Acetonitrile was added dropwise at 0 to + 6 ° C over 45 minutes. After 48 hours at 24 ° C, in addition to oxazoline, N-β-hydroxyethyl-benzamide was still discernible in thin-layer chrocatography. Therefore, an additional 20 mmol of triphenylphosphine dibromide in acetonitrile was added at 0 ° C over 30 minutes and then filtered and washed with acetonitrile. After the filtrate had been evaporated off, the partially crystalline residue was shaken with 200 ml of CH ₂ Cl ₂ and 120 ml of 5 N NaOH and re-extracted with CH ₂ Cl ₂ . After drying (Na ₂ SO ₄ ) and evaporating the CH ₂ Cl ₂ phase, the residue was extracted with 3 × 100 ml of ether and the extract was distilled in a Kugelrohr, 1.3 g (4 4, 2%) of 2-phenyl- Δ ² -oxazoline were obtained.

Example 2 2-Benzyl-Δ ² -oxazoline

a) To 1.79 g (0.01 mol) phenylacetic acid, 3.14 g (0.012 mol) triphenylphosphine and 1.39 ml (0.01 mol) triethylamine in 40 ml abs. Acetonitrile was 0.96 ml (0.01 mol) CCl at + 8- + 10 ° C with stirring. in 10 ml abs. Acetonitrile was added dropwise with stirring over 10 minutes and stirred at 24 ° C for 20 hours. After evaporation, extraction with 3 × 100 ml of hexane and Kugelrohr distillation at 145-150 ° C / 16 mm, 1.4 g (87%) of pure 2-benzyl

Δ ² -oxazoline obtained.

b) In an analogous experiment with N, N-diisopropyl-ethylamine instead of triethylamine, about 65% of 2-benzyl-Δ ² -oxazoline were obtained.

^" liK Example 5 2-Benzyl-Δ ² -oxazoline

a) To 3.58 g (0.02 mol) of N-3-hydroxyethyl-phenylacetic acid amide, 5.25 g (0.02 mol) of triphenylphosphine in 63 ml of abs. 1,2-dichloroethane were at 3.483 g (0.02 mol) diethyl azodicarboxylate in 10 ml of abs. 1,2-dichloroethane was added dropwise within 15 minutes and the mixture was stirred at 24 ° for 1 h. After evaporation, the residue was distilled at 160-165 ° / 20 mm in a Kugelrohr, 2.34 g of crude 2-benzyl-Δ ² -oxazoline being obtained, but which still contained about 10% of diethyl hydrazo-dicarboxylate, which at filtration in toluene-ethyl acetate over a short column of Al ₂ O ₃ (AV) was removed.

1,2-Dichloräthan innerhalb von 10 Minuten bei +3°0 unter Rühren zugetropft und 18 h über Nacht bei 24ºC gerührt. Nach Abdampfen wurde der Rückstand in 30 ml 1,2-Dichloräthan mit 20 mlb) 0.537 g (0.003 mol) of N-β-hydroxyethyl-phenylacetic acid amide and 1.25 ml (0.009 mol) of triethylamine in 20 ml of abs. Acetonitrile was a suspension of abs in 15 ml

1,2-dichloroethane was added dropwise with stirring over the course of 10 minutes at + 3 ° C. and the mixture was stirred at 24 ° C. for 18 hours overnight. After evaporation, the residue was dissolved in 30 ml of 1,2-dichloroethane with 20 ml

2 N NaOH shaken, the aqueous phase extracted with CH ₂ Cl ₂ and the organic phase dried (Na ₂ SO ₄ ). After evaporation and extraction of the residue with 5 × 30 ml of pentane, 0.345 g (73%) of 2-3enzyl-Δ ² -oxazoline were obtained, in which traces of triphenylphosphine oxide could still be detected.

Example 4 2-Benzyl-4,4-dimethyl-Δ ² -oxazoline

To 2.77 g (0.02 mol) of phenylacetic acid, 1.9 ml (0.02 mol) of 2-amino-2-methyl-1-propanol, 12.59 g (0.048 mol) of triphenylphosphine and 27.6 ml ( 0.160 mol) N, N-diisopropylethylamine in 150 ml abs. Acetonitrile was stirred at + 3 ° C with 3.9 ml (0.04 mol) of CCl ₄ in -τ0 ml abs. Acetonitrile was added dropwise with stirring within 10 minutes. I. After 15 minutes at + 4 ° C and 24 hours at 27 ° C was removed evaporates, the residue is extracted with 4 × 300 ml of CH ₂ Cl ₂ -hexane and evaporated. The partially crystalline residue (6.21 g) was distilled in a Kugelrohr at 145-155 ° C / 15 mm, whereby 2.6 g (69%) of pure 2-benzyl-4,4-dimethyl-Δ ² -oxazoline were obtained.

Example 5 2- (3-pyridyl) -4,4-dimethyl-Δ ² -oxazoline

To 2.46 g (0.02 mol) of nicotinic acid, 1.9 ml (0.02 mol) of 2-amino-2-methyl-1-propanol, 22.2 ml (0.16 mol) of triethylamine and 14.69 g (0.056 mol) triphenylphosphine in 100 ml abs. Acetonitrile was 3.9 ml (0.04 mol) CCl at + 3 ° C within 10 minutes. in 6 ml abs. Acetonitrile was added dropwise with stirring. After 4 h at +9 C and 18 h at 24 ° C, the mixture was filtered, the precipitate was washed with acetonitrile and the filtrate was evaporated. The partially crystalline residue was extracted with 4 × 150 ml of CH ₂ Cl ₂ -hexane, evaporated and the residue was distilled in a bulb tube at 120 C / 0.5 mbar, 2.6 g (73.8%) of 2- (3rd -Pyridyl) -4, -4-dimethyl- Δ ² -oxazoline were obtained.

Example 6 2-phenyl-4-carbomethoxy-5-methyl-Δ ₂ -oxazoline

2.44 g (0.02 mol) of benzoic acid, 3.39 g (0.02 mol) of L-threonine methyl ester hydrochloride and 13.94 ml (0.1 mol) of triethylamine in 50 ml of abs. Acetonitrile was stirred at 24 ° C for 30 minutes, then 6.75 ml (0.07 mol) of CCl. added and then a solution of 15.74 g (0.06 mol) triphenylphosphine in 200 ml abs. Acetonitrile was slowly added dropwise at 26 ° C over 3 hours. After a further 16 hours at 24 ° C the mixture was filtered, washed with acetonitrile and the filtrate evaporated. After adding 150 ml of H ₂ O, the mixture was extracted with 3 × 100 ml of ether, the ether phase was dried (Na ₂ SO ₄ ) and concentrated to 150 ml and finally to 30 ml, a total of 12.8 g of triphenylphosphine oxide crystallizing out. The filtrate was evaporated and the residue (7.1 g) on 350 g Al ₂ O ₃ , (basic, AV) with hexane-toluene (1: 2) chromatographed, the first 300 ml of Zluat approx. 1 g triphenylphosphine and the next

1 Itr. Eluate 2.5 g (57% pure 2-phanyl - 4-carbomethoxy-5-methyl¬

Δ ² -oxazoline added.

Example 7 2-Benzyl-benzoxazole

To 4.08 g (0.03 mol) of phenylacetic acid, 3.27 g (0.03 mol) of o-aminophenol, 23 and 6 g (0.09 mol) of triphenylphosphine and 16.6 ml (0.12 mol) of triethylamine in 100 ml abs. Acetonitrile, 5.8 ml (0.06 mol) of CCl ₄ in a little acetonitrile were added at + 3 ° C. with stirring and under an argon atmosphere and the mixture was stirred at 24 ° C. for 20 hours. Since not all had been implemented, another 2.9 ml (0.03 mol) of CCl ₄ were added at 0 ° C and the mixture was stirred at 24 ° C for 16 hours. After filtration, washing with acetonitrile, the mixture was evaporated and the residue was taken up in 200 ml of CH ₂ Cl ₂ and 100 ml of 2 N NaOH and the alkaline phase was subsequently extracted with CH ₂ Cl ₂ . After drying (Na ₂ SO ₄ ) and evaporation of the CH ₂ Cl ₂ phase, the residue was extracted with boiling CH ₂ Cl ₂ -hexane, which gave 3.26 g of brown oil after evaporation, which was distilled in a Kugelrohr 2nd , 7 g (43%) of 2-bensylbenzoxazole gave (C ₁₄ H ₁₁ NO) C calc. 80.36, Found 79.87; H Ber. 5.3, Found 5.41; N Ber. 6.89, Found 6.55).

Example 8

2-benzyl-5, 6-dihydro-4H-1,3-oxazine

To 2.72 g (0.02 mol) of phenylacetic acid, 1.53 ml (0.02 mol) of 3-hydroxy-1-propylamine, 1-4.688 g (0.056 mol) of triphenylphosphine and 22.2 ml (0.16 mol ) Triethylamine in 100 ml abs. Acetonitrile was at 0 ° C with stirring and under argon within 10 minutes 3.9 ml (0.04 mol) of CCl ₄ in 10 ml of abs. Acetonitrile added dropwise. After stirring at 24 ° C for 72 h, filtered, with abs. Acetonitrile wash and evaporated. The residue was extracted hot several times with CH ₂ Cl ₂ -hexane and, after filtration, the extracts were distilled in a Kugelrohr, 1.8 g (51.4%) of pure 2-benzyl-5,6-dihydro-4H-1,3- oxazin were obtained (C calc. 75.4, found 75.33; H calc. 7.48, found 7.75; N calc. 7.99, found 7.81).

Example 9 2-PhenyI- Δ ² -thiazoline

To 3.66 g (0.03 mol) of benzoic acid, 3.41 g (0.03 mol) of β-mercaptoethylamine hydrochloride, 16.63 ml (0.12 mol) of triethylamine and 23.599 g (0.09 mol) of triphenylphosphine in 100 ml abs. Acetonitrile was added dropwise at 0 ° C in 5.8 ml (0.06 mol) of CCl ₄ in 20 ml of acetonitrile over 15 minutes with stirring and under argon and stirred at 24 ° C for 16 hours. Since amide was still to be detected, a further 4.2 ml (0.03 mol) of triethylamine and 2.9 ml (0.03 mol) of CCl _{4 were} added at 0 ° C. and stirring was continued at 22 ° C. for 18 hours. After working up with CH ₂ Cl ₂ , 2 N NaOH, the organic residue was boiled with 4 × 150 ml of toluene, the extracts were evaporated and distilled in a bulb tube, 2.2 g (45%) of pure 2-phenyl-

Δ ² -thiazoline were obtained.

Example 10 2-phenyl-Δ ² -imidazoline

To a solution of 1.34 ml (0.02 mol) of 1,2-diaminoethane, 4.8 ml (0.05 mol) of CCl ₄ and 8.36 ml (0.06 mol) of triethylamine in 100 ml of abs. Acetonitrile was a solution of 2.44 g (0.02 mol) of benzoic acid and 12.58 g (0.048 mol) of triphenylphosphine in 200 ml of abs within 6 h. Acetonitrile was added dropwise with vigorous stirring and under Argo, a white precipitate being formed after about 1.5 hours. After a further 18 h at 24 ° C., the mixture was evaporated and the residue was taken up in CH ₂ Cl ₂ /20% NaOH and repeatedly extracted with CH ₂ Cl ₂ . After evaporation of the CH ₂ Cl ₂ extracts and Kugelrohr distillati on at l8θ-190 ° C / l_r, 3ar were 1, 3 * 4 g (-40, 9%)

Obtain 2 pure 2-phenyl-Δ - imi dazolin.

Example 11 1-Methyl-2-phenyl-Δ ² -imi dazolin

In the analogous test using the N ¹ -methyl-1, 2-diaminoethane instead of 1, 2-diaminoethane, 1.6 g (50%) of 1-methyl-2-phenyl-Δ ² -imi were obtained after the distillation get ol olin.

Example 12 2-Anιlino- Δ ² -oxazoline

To 3.6 g (0.02 mol) of N-2-hydroxyethyl-Nlphenyl-urea, 8.4 ml (0.06 Hol) of triethylamine, 5.8 ml (0.06 mol) of CCl ₄ in 100 ml of abs. Acetonitrile-pyridine (1: 1) were stirred with stirring 7.86 g (0.03 mol) triphenylphosphine in 50 ml abs. Acetonitrile-pyridine was added dropwise at + 10 ° for 3 hours and stirred at 20 overnight. After evaporation, the residue was taken up in CH ₂ Cl ₂ /20% NaOH and only CH ₂ Cl _{2 was} extracted several times. After the CH ₂ Cl ₂ extracts had been dried and evaporated, the residue was extracted with hot water and the crystals which separated out on cooling were recrystallized again from diisopropyl ether. Schp. 117-119 °. Yield 0.81 g (50%).

Example 13

2-Anilino-Δ ² -thiazoline The substance was prepared completely analogously to Example 12 starting from N-2-mercaptoethyl-N'-phenylurea. 2-Anilino-Δ ² -thiazoline was recrystallized from dilute ethanol.

Schp. 163-169 °. Yield 40%. Example 1 4

2-Benzyl-Δ ² -4,5,6,7-tetrahydro-oxazepine

To 1.36 g (0.01 mol) of phenylacetic acid, 0.89 g (0.01 mol) of 4-amino-1-butanol, 4.2 ml (0.03 mol) of triethylamine and 2.9 ml (0, 03 mol) CCl ₄ in 100 ml abs. Acetonitrile pyridine (3: 1) were 7.86 g (0.03 mol) triphenylphosphine in 100 ml abs. Acetonitrile was added dropwise with stirring over 8 hours. After standing overnight, the mixture was evaporated and the residue was washed several times with hexate. or CH ₂ Cl ₂ -hexane extracted. The combined eexan extracts were distilled in a bulb tube at 150 ° / 1 mbar, 0.85 g (45%) of 2-benzyl-Δ ² -4,5,6,7-tetrahydrooxazepine being obtained as a colorless oil.

Example 15 2, -4-Diphenyl- Δ ² -oxazoline

To 1.22 g (0.01 mol) of benzoic acid and 1.37 g (0.01 mol) of D (-) - 2-amino-2-phenylethanol in 50 ml abs. Acetonitrile / pyridine (1: 1), 2.8 ml (0.03 mol) CCl ₄ and 1.39 ml (0.01 Hol) triethylamine were 2.62 g (0.01 mol) triphenylphosphine in 20 ml abs. Acetonitrile-pyridine (1: 1) was added dropwise over 3 hours while stirring. Then 2.78 ml (0.02 mol) of triethylamine were added to the reaction solution and a solution of 5.24 μg (0.02 mol) of triphenylphosphine solution in 40 ml of abs. Acetonitrile-pyridine (1: 1) for 3 hours. After stirring for a further 18 hours at 24 °, the mixture was evaporated and the residue was extracted with 500 ml of ice-cold 2N NaOH and 150 ml of toluene and extracted again with toluene. After drying and evaporation, the residue was placed in toluene

Chromatograph silica gel (E. Merck 40% H ₂ O), 1.56 g

(70%) pure, oily 2,4-diphenyl-Δ ² -oxazoline were obtained. Example 16 p-phenylene-2,2'-bis (Δ ² -oxazoline)

To a suspension of 1.66 g (0.01 mol) terephthalic acid, 1.22 g (0.02 mol) ethanolamine, 11.15 ml (0.08 mol) triethylamine and 7.5 ml (0.08 mol) CCl ₄ in 100 ml abs. Acetonitrile pyridine (1: 1) were 15.74 (0.06 mol) triphenylphosphine in 100 ml abs. Acetonitrile-pyridine (1: 1) was added dropwise with stirring over the course of 3 hours, during which almost everything dissolved. After stirring overnight, evaporation and boiling of the residue with toluene, 14.3 g of residue were obtained from the toluene solution. In the

Extraction of the triphenylphosphine oxide with a little isopropanol left 1.51 g (70%) of pure p-phenylene-2,2'-bis- (Δ ² -oxazoline). Schp. 233-237 °.

Example 17 2- (12-Hydroxyheptadecyl) - Δ ² oxazoline

To 3.0 g (0.01 mol) of purified 12-hydroxystearic acid, 0.61 g (0.01 mol) of ethanolamine, 4.2 ml (0.03 mol) of triethylamine and 2.9 ml of CCI ₄ (0.03 Hol) were abs in 50 ml. Acetonitrile-pyridine (1: 1) dissolved and 7.86 g (0.03 mol) triphenylphosphine in 60 ml abs. Acetonitrile-pyridine (1: 1) was added dropwise over 4 hours while stirring. After stirring overnight with working up with 2N NaOH and toluene, the organic phase in toluene was chromatographed on silica gel (E. Merck 40% H ₂ O), 2.083 g (64%) of pure 2- (12-hydroxyheptadecyl) - Δ ² -oxazoline were obtained.

Example 18 2- (2'-hydroxyphenyl) - Δ ² oxazoline

To 1.38 g (0.01 mol) salicylic acid, 0.61 g (0.01 mol) ethanolamine and 2.9 ml (0.03 mol) CCl, in 50 ml abs. Acetonitrile pyridine (1: 1) were 7.86 g (0.03 mol) triphenylphosphine and 4.2 ml (0.03 mol) triethylamine in 6θml abs. Acetonitrile pyridine (1: 1) added dropwise with stirring for about 6 hours. The mixture was then stirred overnight and toluene / sat. NH ₃ solution added. The organic phase was dried, evaporated and distilled in a bulb tube, 0.9789 (6θ%) 2- (2'-hydroxyphenyl) Δ ² -oxazoline, Sdpt. 95 ° (0.1 Torr) were obtained.

Example 19

2-benzyl-3,4,5,6-tetrahydropyrimidine hydrochloride

To a solution of 0.74 g (0.01 mol) 1,3-diaminopropane, 1.01 g (0.01 mol) triethylamine and 6.15 g (0.04 mol) CCl ₄ in 50 ml abs. Acetonitrile-pyridine (1: 1) was a solution of 1.36 g (0.01 mol) phenylacetic acid and 2.62 g (0.01 mol) triphenylphosphine in 50 ml abs. Acetonitrile / pyridine (1: 1) was added dropwise at 2 * 4 within 3 hours with stirring and the cloudy reaction mixture was stirred at 24 ° for a further 2 hours. Then another 5.24 g (0.02 mol) triphenylphosphine in 50 ml abs. Acetonitrile / pyridine (1: 1) was added dropwise with stirring over the course of 3 hours and the mixture was stirred overnight. After evaporation of the reaction mixture was abs in 200 ml. Dissolved ethanol and mixed with 0.54 g (0.01 mol) of sodium methylate, whereby NaCl failed. After filtering off and evaporating the filtrate, the residue was extracted into 200 ml of CH ₂ Cl ₂ with 3 × 75 ml of 2N HCl, the aqueous phase was carefully evaporated in vacuo and the 2-benzyl-3,4,5,6-tetrahydropyriminedine hydrochloride recrystallized from isopropanol. Yield: 1.33 g (63%). Melting point: 211-212 °. Example 20 2-Anilino-Δ ² -oxazoline

To a solution of 1.8 g (0.01 mol) of N-β-hydroxyethyl-N'-phenylurea, 2.3 g (0.015 mol) of CCl ₄ , 1.01 g (0.01 mol) of triethylamine in 50 ml Section. Acetonitrile / pyridine (1: 1) a solution of 3.93 g (0.015 mol) triphenylphosphine in 50 ml abs. Acetonitrile / pyridine (1: 1) was added dropwise over a period of 3 hours, during which the reaction mixture turned yellow and triethylamine hydrochloride crystallized out. After standing overnight, the mixture was evaporated in vacuo and the partially crystalline residue was shaken with 200 ml of ether and 100 ml of 10 N KOH, the ether phase was separated off and extracted again with 3 × 50 ml of ether. After drying (Na ₂ SO ₄ ) and concentration of the ether extracts to 50 ml, 3.02 g of triphenylphosphine oxide crystallized out. After evaporating and dissolving in hot diisopropyl ether, 1.09 g (67%) of 2-anilino-

Δ ² -oxazoline, melting point 117-118 °.

Claims

Claim Process for the preparation of Δ ² -N heterocycles of the general Formula I,

in the v 1 to 4 R ₁ (for v = 1) is hydrogen which may be replaced by hydroxy, Amino, nitro, fluorine, chlorine, bromine, C ₁ -C ₄ -alkoxycarbonyl, DiC ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkylaminocarbonyl, tri-C ₁ - C ₄ -alkylsilyloxy-, tetrahydropyranyloxy or benzoyloxy-substituted radicals alkyl with 1-19 carbon atoms, aralkyl with 7-10 carbon atoms or cycloalkyl with 5-7 carbon atoms, an oxoalkyl radical with 1-6 carbon atoms, an aryl radical or a 5- or 6-membered ether cycle with 1 -3 N, O or S heteroatoms, R ₁ (for v = 2) is an arylene radical, optionally by hydroxy, Oxo, amino, nitro, fluorine, chlorine, bromine, tri-C ₁ -C ₄ -alkylsilyloxy, benzoyloxy-substituted alkylene - (CH ₂ ) -, where m can be 1 to 6, or the rest -CH = CE-, R ₁ (for v = 3 or 4) is a 3 or 4-membered benzene radical or optionally by hydroxy, oxo, amino, nitro, fluorine, Chlorine, bromine, tri-C ₁ -C ₄ -alkylsilyloxy, tetrahydropyranyloxy, Benzoyloxy substituted trihydric or tetravalent alkylene - (CH ₂ ) - _m , where m can be 1 to 6, D an imino residue or a direct bond, Y is oxygen, sulfur, imino or N- (C ₁ -C ₄ -alkyl) imino, Z the rest (CR ₆ R ₇ ), where n can be 0 to 3, R _{2 is} hydrogen, optionally substituted by a hydroxy or amino group, alkyl having 1-6 C atoms, C _1- C ₄ -A-koxycarbonyl, cyano or di-C _1- C ₄ -alkylaminocarbonyl, R ₃ , R ₄ , R ₅ , R ₆ , R _{7 are} hydrogen, alkyl which is optionally substituted by a hydroxyl or amino group and has 1-6 C atoms or aryl, R ₃ and R ₄ together trimethylene, tetramethylene or 1,3-butadienylene, if R ₂ and R ₅ together represent a direct bond, from compounds of the general formula II.

in which R ₁ , D and v have the meanings given above, X represents an oxygen or sulfur atom or the rest and

R _{8 is} hydroxy, a C _1- C ₆ alkoxy radical, a C _1- C ₆ alkylthio radical, an aryloxy or thio radical, an aralkyioxy or thio radical with 7-10 C atoms, a C _1- C ₄ - Represent trialkylsilyloxy or thio radical or a tri-C ₇ -C ₁₀ aralkylsilyloxy or thio radical, and amines of the general formula III III,

in which R ₂ , R ₃ , R ₄ , R ₅ , Y and Z have the meanings given above, characterized in that using organic phosphines or phosphonium salts and perhalogenated hydrocarbons or ketones or using azodicarboxylic acid diesters in the presence of tertiary amines implements.