HU189226B - Process for producing basic oxime-ethers - Google Patents

Abstract

An improved process for the preparation of basic oxime ethers of the general Formula I <IMAGE> /wherein R is a phenyl group optionally substituted by one to three halogen atom/s/ and/or lower alkoxy group/s/; R<1> and R<2> each are hydrogen or together from a valence bond; A is lower alkylene; R<3> and R<4> each stand for hydrogen or lower alkyl or together with the adjacent nitrogen atom they are attached to form a 5-8 membered heterocyclic ring which may optionally contain a further oxygen or nitrogen atom and/or may be optionally substituted by lower alkyl, phenyl or phenyl-lower alkyl, and n is 3, 4, 5, 6 or 7/ and acid addition salts thereof comprises reacting an oxime of the general Formula II <IMAGE> with a compound of the general Formula III <IMAGE> (where Hal is a halogen atom) or an acid addition salt thereof in the presence of an alkali metal lower alkoxide and an aromatic organic hydrocarbon solvent.

Description

The present invention relates to a new and improved process for the preparation of basic oxime ethers.

More particularly the basic oxime ethers of the process (I) of formula (wherein R is optionally substituted with one to three halogen atoms and / or substituted C1-4 alkoxy; R ¹ and R ² each signify hydrogen or together form a chemical bond, A is C 1-4 alkylene; R ³ and R ⁴ are each hydrogen or C 1-4 alkyl, or R ³ and R ^{4 taken} together with the adjacent nitrogen atom to which they are attached may contain 5 to 7 membered optionally further oxygen or nitrogen heteroatoms; and optionally form a heterocyclic ring substituted with C 1 -C 4 alkyl, phenyl or phenyl (C 1 -C 4 alkyl) and n is 3,4,5,6 or 7) and their acid addition salts.

The compounds of formula (I) are known to be useful in medicine by virtue of their antidepressant, antiparkinsonian and local anesthetic activity (Hungarian Patent No. 169,298, No. 1). According to the cited patent, the compounds of the formula I are, inter alia, the compounds of the formulas II and III (wherein Hal is halogen and R, R ¹ , R ² , R ³ , R ⁴ and n by reaction with an inert solvent in the presence of a basic condensing agent. In the examples of the patent, only organic solvents (toluene, ethanol, benzene or xylene) are used as the inert solvent, while sodium hydride, sodium amide and metal sodium are used as the basic condensing agent. According to the description, alkali metal hydroxides can also be used as basic condensing agents without experimental support; in this case, the role of the solvent is water. For the use of alkali metals, an alcoholic medium is recommended in U.S. Patent No. 169,298. Hungarian patent specification.

The process described in the above-mentioned patent, especially when implemented on larger scale under industrial conditions, has the following disadvantages:

The haloalkylamines of formula (III) are for use only as a base and the bases of formula (III) are highly unstable for dimerization or polymerization; the degree of specific utilization of the devices during the reaction is unfavorable;

the reaction time is long (12-16 hours); the final product is isolated by complex methods (decomposition of sodium hydride or sodium amide, acidic and alkaline extractions or by-passes, etc.);

the purification is carried out by a fine vacuum distillation process which requires sophisticated equipment;

the hydrogen gas produced in the reaction is explosive and the ammonia evolved pollutes the environment;

in some cases, the reaction is isomerized.

The latter drawback is illustrated by the fact that 2- (E) - (-) p-chlorophenylmethylene (-1 - [(E) -3'-diisopropylaminopropoxyimino)] - cyclohexane 169 298 No. 1 In addition to the expected product, a considerable amount of material of unknown structure is obtained, the physicochemical parameters of which are substantially different from those of the desired compound. The UV spectrum of the two spectra of compounds it has been found that the _present value X of the desired compound is 280 nm (ε = 17456.15) is _present in the unknown material X: 243 nm (ε = 1245).

This large difference proves that an undesirable side reaction (isomerization) occurred during the conversion.

No. 169,298. The Hungarian patent for the purpose of this invention relates to the preparation of pharmacologically active novel compounds, and its patent purpose was to produce a sufficient amount of substance for the chemical identification and pharmacological action of the new compounds. The object of the present invention is disclosed in U.S. Pat. From the method described in the Hungarian patent, developing a process that is economically feasible on a commercial scale and which satisfies the requirements of environmental protection, energy saving and economy can be eliminated.

The present invention relates (I) have basic oxime ethers of the formula (which formula III where R is phenyl optionally substituted with one to three halogen atoms and / or substituted C 1-4 alkoxy group; individually hydrogen or together form a valence bond, ^R1 and ^R2, A is 1 R ³ and R ⁴ each represent hydrogen or C 1-4 alkyl, or R ³ and R ⁴ together with the adjacent nitrogen to which they are attached form a 5-7 membered, optionally further oxygen or nitrogen heteroatom, and they form a heterocyclic ring substituted with C 1-4 alkyl, phenyl or phenyl (C 1-4 alkyl) and n is a 3,4,5,6 or 7) and an oxime of formula II for the preparation of their acid addition salts wherein R, R ¹ , R ² and n are as defined above and of formula III by reaction of a logene compound (wherein Hal is halogen and A, R ³ and R ⁴ are as defined above) by reacting the oxime of formula II with a halogen compound of the formula III or an acid addition salt thereof. in the presence of an alkali metal alcoholate and an aromatic organic hydrocarbon, and optionally converting the resulting compound of formula (I) into an acid addition salt in a known manner.

It has now been found that the reaction of the oximes of the formula II with the halogen compounds of the formula III or their acid addition salts in the presence of an alkali metal alcohol and an aromatic sulfur hydrocarbon results in a very short time, in excellent yield and free of isomers. pure products are produced.

As used herein, the term "lower alkoxy" refers to straight or branched C1-C4 alkoxy groups (e.g., methoxy, ethoxy, η-propoxy, isopropoxy, etc.).

189,226 special vacuum vacuum distillation purification, no explosive reactions) and suppresses side reactions in very good yield.

The following examples illustrate the details of our process without limiting the invention to the following examples:

The term "halogen" includes fluorine, bromine, chlorine and iodine. The term "lower alkylene group" refers to straight or branched chain alkylene groups having 2 to 4 carbon atoms (e.g., ethylene, trimethylene or 1-methylethylene, etc.). The term "lower alkyl" refers to straight or branched chain alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, etc.).

A 5-8 membered heterocyclic group formed by AR ³ , R ⁴ and a neighboring nitrogen atom, optionally containing additional oxygen or nitrogen heteroatoms and optionally substituted, e.g. morpholino, pyrrolidino, piperidino, N-methylpiperazino, N-phenylpiperazino or N-benzylpiperazino, and the like. may.

n is preferably 4-5.

The acid addition salts of the compounds of formula (I) may be pharmaceutically acceptable addition salts with inorganic or organic acids (e.g., hydrochlorides, hydrobromides, sulfates, maleates, fumarates, acetates, lactates, etc.).

Sodium methylate, sodium ethylate, potassium methylate, potassium ethylate or potassium tert-butylate are preferably used as alkali metal alcoholates in the process of the present invention. The aromatic organic hydrocarbon is preferably benzene, toluene or xylene or a mixture thereof.

In a particularly preferred embodiment of the process, the reaction of the compounds of formula (II) and (III) can be carried out in the presence of sodium methylate and toluene, xylene or benzene.

The reaction is preferably carried out under heating, especially at the boiling point of the reaction mixture. Advantageously, the lower alcohol formed during the reaction, together with the aromatic organic hydrocarbon, is distilled from the reaction mixture. The reaction takes place after a very short reaction time of 1-2 hours.

The starting material of the formula (III) may also be used in the form of its acid addition salt, preferably its addition salt with an inorganic acid, most preferably its hydrochloride.

The reaction mixture is worked up by methods known per se. Alternatively, the reaction mixture is poured into water and then, after washing, freed of solvent. Alternatively, the compound of formula (I) may be isolated in the form of its acid addition salt. The salt formation can be carried out in a manner known per se by reaction with the appropriate acid in an inert solvent medium.

According to the process of the present invention, the following compounds are particularly preferred:

2 - [(E) -phenylmethylene)] - 1 - [(E) - (3'-diisopropylaminopropoxyimino] -cyclohexane;

2 - [(E) - (p-chlorophenylmethylene)] - 1 - [(E) - (3'-diisopropylaminopropoxyimino)] - cyclohexane;

2-benzylidene-1- (2'-diisopropylaminoethoxyimino) cycloheptane.

The process according to the invention has the advantage that it can be advantageously carried out under operating conditions (short reaction time, simple isolation, complex and

Example 1

2 - [(E) - (2 ', 4'-Dichlorophenylmethylene) - [- (E) -4'-benzylpiperazinylpropoxyimino)] - cyclohexane

An apparatus equipped with a stirrer was charged with 150 cm ^{3 of} anhydrous toluene, 5.4 g (0.01 mol) of sodium methylate and 27.02 g (0.1 mol) of 2 - [(E) -2 ', 4'-dichlorophenyl]. methylene) j-cyclohexane-l-one- (E) -oxime. Approx. 30 cm ³ methanol: toluene mixture was distilled off, followed by refluxing (0.11 mole) of N-benzyl-N '27.7 g of - (3-chloropropyl) piperazine in 50 cm ³ toluene was added, and reacted for 1-2 hours. The reaction mixture was poured into 150 cm ^{3 of} ice water and the toluene solution was washed with neutral solvent in vacuo. Yield: 41.94 g (86.2%)

2- (E) -butenedioate (1/2) m.p. 197-200.5 ° C Analysis for C ₃₅ H ₄ iCl ₂ N ₃ O ₉ (718.65):

Calculated: C, 58.5; H, 5.75; Cl, 9.86; N, 5.84; Found: C, 58.4; H, 5.69; Cl, 9.79; N, 5; 87%

UV .: = 273 nm (ε = 15 409)

Example 2

2 - [(E) - (m-chlorophenylmethylene)] - [(E) - (4'-)

benzylpiperazinyl-ethoxyimino)] -cyclohexane

Weigh into an apparatus equipped with a stirrer

23.57 g (0.1 mol) of 2 - [(E) - (m-chlorophenylmethylene)] cyclohexan-1-one (E) -oxime in 150 cm ^{3 of} xylene, 18.9 g (0, Sodium methoxide (35 moles) and 30 cm ^{3 of} xylene: methanol are distilled under atmospheric pressure with stirring. Cooled below the boiling point of the reaction mixture, 34.2 g (0.11 mol) of N-benzyl-N '- piperazine diklórhidrátot (2-chloroethyl) was added and after a further 50 cm ³ solvent was distilled off, boiled for some hours, After cooling to 20 [deg.] C., it is poured into 200 cm <^{3> of} ice-water, the xylene layer is washed neutral with water and concentrated in vacuo.

Yield: 38.25 g (87.3%)

2- (E) -butenedioate (1/2) Mp 197-199.5 ° C

Analysis for C ₃₄ H ₄ ClN ₃ O ₄ (670.2):

Calculated: C, 60.94; H, 6.02; Cl, 5.29; N, 6.27; Found: C, 61.04; H, 6.13; Cl, 5.25; N, 6. 31%

UV .: _max = 274 nm (ε = 15246)

Example 3

2- (E) -phenylmethylene-1- (E) -4'-phenyl-piperazinyl-propoxyimino) -cyclohexane

20.1 g (0.1 mol) of 2- (e) -phenylmethylene-cyclohexan-1-one (e) -oxime and 25.0 g (0.105 mol) of N-phenyl-N '- (3- 3189,226

-chloropropyl) -piperazine, otherwise

Example 1 was followed.

Yield: 35.19 g (87.2%)

Chlorohydrate M.p .: 190-194 ° C Analysis calculated for C ₂₆ H ₃₄ ClN ₃ O (440.04): C, 70.97; H, 7.79; Cl, 8.06; N, 9.55. % Found: C: 71.06% H: 7.83% Cl: 8.11% N: 9.61%

Example 4

2- (E) - (o-Chloro-phenylmethylene) -1 - [(E) - (4'-benzyl-piperazinyl-propoxyimino) -cyclohexane

23.57 g (0.1 mol) of 2- (E) - (o-chlorophenylmethylene)] -cyclohexan-1-one (E) oxime, 35.72 g (0.11 mol) of N Starting from benzyl N '- (3-chloropropyl) piperazine dichlorohydrate, proceed as in Example 2. Yield: 37.71 g (83.4%)

2- (E) -butenedioate (1/2) m.p. 197-201 ° C Analysis calculated for C ₃₅ H ₄₂ ClN ₃ O ₄ (68.2): C, 61.44; H, 6; 15% Cl: 5.19% N: 6.14% Found: C: 61.25% H: 6.22% Cl: 5.16% N: 6.23%

UV:? _Max = 269 nm (ε = 11573)

Example 5

2- (E) -phenylmethylene-1-f (E) - (4'-benzyl-piperazinyl-eloxyimino) -cycloheptane

21.53 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime, 26.16 g (0.11 mol) of N-benzylN '- (2- starting from chloroethyl) piperazine according to Example 1.

Yield: 38.8 g (93.2%)

Dichlorohydrate M.p .: 206-209 'C

Analysis calculated for C ₂₇ H ₃₆ CIN ₃ O (489.62): C, 66.23; H, 7.43; Cl, 14.56; N, 8.58; Found: C, 66.12. % H: 7.15% Cl: 14.62% N:

8.61%

UV: λ _max = 262 nm (ε = 17 012)

Otherwise, starting from diisopropylamino-3-chloropropane, the procedure of Example 1 was followed.

Yield: 37.14 g (98.5%)

2- (E) -butenedioate (1/1) m.p. 87-89.5 ° C Analysis calculated for C ₂₆ H ₃₇ ClN ₂ O ₅ (493.06): C, 63.34; H: 7.56% Cl: 7.19% N: 5.68% Found: C: 63.22% H: 7.49% Cl: 7.18% N: 5.72%

UV: λ _max = 280 nm (ε = 17,456)

Example 8

2- (Z) -phenylmethylene-1 - [(2'-diisopropylaminoethoxyimino)] - cycloheptane

Starting from 21.53 g (0.1 mol) of 2- (Z) phenylmethylene-cycloheptan-1-one (E) -oxime and 22.02 g (0.11 mol) of 1-dimethylamino-2-chloroethane hydrochloride and proceed as in Example 2.

Yield: 31.3 g (91.4%)

2- (E) -butenedioate (1/1) Mp: 117-120 ° C

Calcd for C ₂₆ H ₃₈ N ₂ O ₅ (458.6) calculated: C 68.09% H 8.35% N 6.11% Found: C: 67.92% H: 8, 42% N: 6.07%

UV: _λmax = 258 nm (ε = _11,182 )

Example 9

2 - [(E) -p-chlorophenylmethylene)] - 1 - [(E) - (2'-dimethylaminoethoxyimino) / - cyclohexane

23.57 g (0.1 mol) of 2 - [(E) - (p-chlorophenylmethylene)] cyclohexan-1-one (E) oxime and 12.24 g (0.105 mol)

Starting from 1-dimethylamino-2-chloroethane, proceed as in Example 1.

Yield: 28.50 g (93.2%)

2- (E) -butenedioate (1/1) Mp: 168.5-171 ° C

Analysis calculated for C ₂₁ H ₂₇ ClN ₂ O _S (422.92): C, 59.64; H, 6.44; Cl, 8.38; N, 6.62; 42% H: 6.38% Cl: 8.27% N: 6.67%

UV: Z _max - 275 nm (ε = 19,292)

Example 6

2- (E) -phenylmethylene-1 - [(E) - (3'-diisopropylaminopropoxyimino)] -cyclohexane

20.13 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexan-1-one- (E) -oxime and 19.53 g (0.11 mol) of 1-diisopropyl-1-amino-3 starting from chloropropane and following the Li example. !

Yield: 33.05 g (96.5%)

2- (E) -butenedioate (1/1) Mp: 130-132 ° C

Analysis (458.61) for C ₂₆ H ₃₈ N O _{2 S} Calculated: C 68.09% H 8.35% N 6.10% Found: C: 67.95% H: 8, 42% N: 6.03%

Example 10

2-Benzylidene-1 - [(E) -2'-dimethylaminoethoxyimino) cycloheptane

Starting from 21.63 g (0.1 mole) of 2-benzylidene cycloheptan-1-one (E) oxime and 16.84 g (0.11 mole) of 2-dimethylamino-1-chloroethane hydrochloride. follow the example.

Yield: 26.96 g (93.5%)

2- (E) -butenedioate (1/1) Mp: 121 'C

Analysis calculated for C ₂₂ H ₃₂ N ₂ O 3 (404.51): C, 65.32; H, 7.97; Ν: 6.93; Found: C, 65.47; H, 7; 82% N: 6.95%

Example 7

2 - [(E) - (p-Chlorophenylmethylene) / - 1 - [(E) - $ '- diisopropylaminopropoxyimino) / - cyclohexane

23.6 g (0.1 mol) of 2 - [(E) -p-chlorophenylmethylene)] cyclohexan-1-one (E) oxime and 19.54 g (0.11 mol)

Example 77

2- (E) -phenylmethylene-1- (E) - (4'-methylpiperazinyl-propoxyimino) -cycloheptane

21.5 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime and 18.55 g (0.105 mol) of N-methylN '- (3-chloropropyl) Starting from piperazine, the procedure of Example 1-4I da is followed, except that the reaction is carried out in benzene instead of toluene. Yield: 34.67 g (93.8%)

2- (E) -butenedioate (1/2) m.p. 204-208 ° C Analysis calculated for C ₃₁ H ₄₃ N ₃ O ₉ (601.71): C, 61.88; H, 6; 98% N, 7.20% Found: C, 61.62; H, 6.87; N, 7.17%.

UV: λ _max = 272 nm (ε = 1370)

Example 12

2- (E) -phenylmethylene-1 - [(E) - (2'-dimethylamino-ethoxyimino) -cycloheptane

21.53 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime and 18.7 g (0.105 mol) of 1-diethylamino-2-chloroethane hydrochloride starting from Example 2, except that the reaction is carried out in toluene instead of xylene. Yield: 27.51 g (87.5%)

2- (E) -butenedioate (1/1) m.p. 86-88 ° C Analysis calculated for C ₂₄ H ₃₄ N ₂ O ₅ (430.53): C, 66.95; H, 7; 96% N, 6.51% Found: C, 67.12; H, 8.04; N, 6.58.

UV:? _Max = 264 nm (ε = 16395)

Example 13

2- (E) -phenylmethylene-1 - [(E) - (2'-diisopropylaminoethoxyimino) -? - cyclohexane

20.13 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexan-1-one (E) -oxime and 18.00 g (0.11 mol) of 1-diisopropylamino-2- otherwise, starting with chloroethane, the procedure of Example 1 was followed.

Yield: 31.71 g (96.3%)

2- (E) -butenedioate (1/1) m.p. 103-105 ° C Analysis calculated for C ₂₅ H ₃₆ N ₂ O 3 (444.58): C, 67.54; H, 8.16. % N, 6.30; Found: C, 67.23; H, 8.32; N, 6.28.

UV:? _Max = 275 nm (ε = 17304)

Example 14

2- (E) -phenylmethylene-1 - [(E) - (3'-dimethylaminopropoxyimino)] - cyclooctane

Starting from 22.93 g (0.1 mol) of 2- (E) -phenylmethylene-cyclooctane-1-one (E) -oxime and 15.11 g (0.11 mol) of 1-dimethylamino-3-chloropropane Example 1 except that the reaction is carried out in benzene instead of toluene.

Yield: 28.40 g (94.5%)

2- (E) -butenedioate (1/1) Mp 136-139 ° C

Analysis for the Formula C ₂₃ H ₃₂ N ₂ O ₅ (416.52): Calculated: C 66.32% H 7.75% N 6.73% Found: C: 65.89% H: 7, 64% N: 6.79%

UV:? _Max = 276 nm (ε = 14395)

Example 15

2- (E) -phenylmethylene-1- (E) - (2'-dimethylamino-2'-methyl-ethoxyimino) -cyclohexane

20.13 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexan-1-one (E) -oxime and 16.6 g (0.105 mol) of 2-dimethylamino-2-methyl-1-chloro- starting from ethane, the procedure of Example 1 was followed.

Yield: 26.9 g (93.9%)

2- (E) -butenedioate (1/1) Mp 113-117 ° C

Analysis calculated for C ₂₂ H ₃₀ N ₂ O ₅ (402.48): C, 65.64; H, 7.51; N, 6.96; Found: C, 65.42; H, 7; 39% N: 6.87%

UV:? _Max = 273 nm (ε = 13475)

Example 16

2- (E) -phenylmethylene-1 - [(E) -2'-dimethylamino-2'-methyl-ethoxyimino)] -cycloheptane

21.53 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime and 16.6 g (0.105 mol) of 2-dimethylamino-2-methyl- Starting from l-chloroethane, the procedure of Example 1 was followed.

Yield: 28.61 g (95.2%)

2- (E) -butenedioate (1/1) m.p. 120-123 ° C Analysis calculated for C ₂₃ H ₃₂ N ₂ O ₅ : C, 66.32; H, 7.75; 73% Found: C, 66.18; H, 7.62; N, 6.65.

UV: λ _max = 262 nm (ε = 17,595)

Example 17

2- (E) -phenylmethylene-1 - [(E) - (2'-diisopropylaminoethoxyimino) -J-cyclooctane

Starting from 22.93 g (0.1 mol) of 2- (E) -phenylmethylene-cyclooctane / (E) -oxime and 1, 22.02 g (0.11 mol) of 1-diisopropylamino-2-chloroethane Example 1.

Yield: 33.22 g (93.3%)

Hydrochloride salt m.p. 158-161 ° C

Analysis calculated for C ₂₃ H ₃₇ ClN _{2 O} (393.0): C, 70.29; H, 9.47; Cl, 9.02; N, 7.13; Found: C, 69.78; H: 9.32% Cl: 9.11% N: 7.32%

UV:? _Max = 276 nm (ε = 14170)

Example 18

2 - [(E) - (p-chlorophenylmethylene)] - 1 - [(E) - (4'-methylpiperazinylpropoxyimino) -? - cyclohexane

23.57 g (0.1 mol) of 2- (E) - (p-chlorophenylmethylene) cyclohexan-1-one (E) -oxime and 18.55 g (0.105 mol) of N-methyl-N Starting from '- (3-chloropropyl) piperazine, proceed as in Example 1, except that xylene is used in the reaction instead of toluene. Yield: 34.49 g (87.6%)

2- (E) -butenedioate (1/2) m.p. 196-199 ° C Analysis for C ₂₉ H ₃ G ClN ₃ O ₉ :

; Calculated: C, 57.28; H, 6.29; Cl, 5.83; N, 6.91; Found: C, 57.32; H, 6.37; Cl, 5.78; N, 6 82%

I UV:? _Max = 278 nm (ε = 16507)

189,226

Example 79

2- (E) - (m-Chlorophenylmethylene) -1 - [(E) - (4'-benzylpiperazinyl-propoxyimino) -N-cycloheptane

24.97 g (0.1 mol) of 2 - [(E) - (m-chlorophenylmethylene)] cycloheptan-1-one (E) oxime and 35.72 g (0.11 mol) of N Otherwise, starting from benzyl N '- (3-chloropropyl) piperazine dichlorohydrate, the procedure of Example 2 was followed.

Yield: 39.02 g (86.5%)

2- (E) -butenedioate (1/2) m.p. 196-198 ° C Analysis calculated for C ₃ H ₄₂ CIN ₃ O, 684.20: C, 61.44; H, 6 18% Cl: 5.18% N: 6.14% Found: C: 61.34% H: 6.32% Cl: 5.17% N: 6.25%

UV: λ, _ηιχ = 274 nm (ε = 13,700)

Example 20

2- (E) -m-methoxyphenylmethylene] -1 - [(E) - (4'-benzylpiperazinylpropoxyimino)] - cyclohexane

The procedure described in Example 1 was carried out with the exception that 26.73 g (0.1 mol) of 2 - [(E) - (m-methoxyphenylmethylene)] 1-one- (E) - oxime and 35.72 g (0.11 mol) of N-benzyl-N '(3'-chloropropyl) piperazine dihydrochloride.

Yield: 37.2 g (83.2%)

2- (E) -butenedioate (1/2) m.p. 190-193 ° C Analysis calculated for C ₃₆ H ₄₅ N ₃ O ₁₀ (679.78): C, 63.61; H, 6; 67% N, 6.18% Found: C, 63.79; H, 6.89; N, 6.12%.

UV: λ, _ηι> = 272 nm (ε = _14,820 )

Example 21

2-j (E) -phenylmethylene] -1- (3'-morpholino-propoxyimino) -cyclohexane

The procedure of Example 1 was carried out with the exception that it was used as starting material

2- (E) -phenylmethylene-1-one (E) oxime (20.13 g, 0.1 mol) and l-chloro-3-morpholinopropane hydrochloride (19.39 g, 0.1 mol) were used.

25.95 g (79%) of the title compound are obtained. 2- (E) -butenedioate (1/1) m.p. 143-145 ° C Analysis calculated for C ₂₄ H ₃₂ N ₂ O ₆ (444.52): C, 64.84; H, 7; 26% N, 6.3% Found: C, 64.70; H, 7.32; N, 6.52.

UV:? _Max = 276 nm (ε = 15400) '

Example 22

2 - [(E) -3 ', 4', 5'-trimethoxyphenylmethylene)] - 1 - [(E) - (4'-methylpiperazinyl-propoxyimino] -cyclohexane

The procedure of Example 1 was carried out with the exception that it was used as starting material

29.13 g (0.1 mol) of 2 - [(E) - (3 ', 4', 5'-trimethoxyphenylmethylene)] - 1-one (E) -oxime and 23.57 g (0.105 mol) N-methyl-N '- (3-chloropropyl) piperazine is used.

Yield: 33.5 g (77.7%)

2- (E) -butenedioate (1/2) m.p. 185-187 ° C Analysis for C ₃₂ H ₄ J N ₃ O ₁₂ (663.70):

Calculated: C, 57.91; H, 6.83; N, 6.33; Found: C, 58.30; H, 6.99; N, 6.52.

UV: _.lambda.max = 294 nm (ε = 20500)

Example 23

2 - [(E) -phenylmethylene-1 - [(E) - (2'-aminoethoxyimino)] -cyclohexane

The procedure of Example 1 was carried out with the exception that it was used as starting material

20.13 g (0.1 mole) of 2 - [(E) -phenylmethylene)] - 1-one (E) oxime and 17.65 g (0.1 mole) of 1-amino-2-chloro- ethane hydrobromide.

21.26 g (87%) of the title compound are obtained. 2- (E) -butenedioate (2/1) m.p. 176-179 ° C Analysis calculated for C ₃₄ H ₄₄ N ₄ O ₆ (604.72): C, 67.53; H, 7; 33% N, 9.27% Found: C, 67.24% H, 7.19% N, 9.31%

UV:? _Max = 275 nm (ε = 18000)

Claims (9)

Claims 1. A method (I) have basic OXYMETER formula (wherein R is optionally substituted with one to three halogen atoms and / or lower alkoxy; are R ^l and R ² each signify hydrogen or together a bond, A is 1-4 R ³ and R ⁴ each independently represent hydrogen or C 1-4 alkyl, or R ³ and R ⁴ together with the adjacent nitrogen atom to which they are attached form a 5-7 membered, optionally further oxygen or nitrogen heteroatom; They form a heterocyclic ring substituted with C 1-4 alkyl, phenyl, or phenyl (C 1-4 alkyl) and n is a 3,4,5,6 or 7) and an oxime of formula II for the preparation of their acid addition salts (wherein R, R ¹ , R ² and n are as defined above) and a halogen compound of formula (III) et (wherein Hal is halogen and A, R ³ and R ⁴ are as defined above), characterized in that the oxime of formula (II) and the halo compound of formula (III) or an acid addition salt thereof are reacted with a lower alkali metal alcoholate. and in the presence of an aromatic organic hydrocarbon, optionally distilling off the resulting alcohol with the organic hydrocarbon, optionally converting the resulting compound of formula (I) to an acid addition salt in a known manner. 2. A process according to claim 1 wherein the alkali metal alcoholate is sodium methylate. 3. A process according to claim 1 or 2 wherein the aromatic organic hydrocarbon is benzene, toluene or xylene or a mixture thereof. 4. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out under heating, preferably at the boiling point of the reaction mixture. 5. The method of any one of claims 1 to 6 189,226 characterized in that the reaction is carried out for 1-2 hours. 6. Process for the preparation of 2 - [(E) -phenylmethylene)] - 1 - [(E) - (3'-diisopropylaminopropoxyimino)] - cyclohexane according to any one of claims 1 to 2 ([(E) -phenylmethylene)] by reaction of -cyclohexan-1-one (E) -oxime and 1-diisopropylamino-3-chloropropane, characterized in that the reaction is carried out in the presence of sodium methylate and toluene. The process of claim 1 for the preparation of 2 - [(E) - (p-chlorophenylmethylene)] - 1 - [(E) - (3'-diisopropylaminopropoxyimino)] - cyclohexane 2 - [(E) ) -chlorophenylmethylene)] -cyclohexan-1-one (E) -oxime and 1-diisopropylamino-3-chloropropane, characterized in that the reaction is carried out in the presence of sodium methylate and toluene. a. The process according to claim 1 for the preparation of 2-benzylidene-1- (2'-diisopropylaminoethoxyimino) cycloheptane by reaction of 2-benzylidene cycloheptanone oxime with 2 diisopropylaminoethyl chloride, characterized in that: the reaction is carried out in the presence of sodium methylate and toluene. 9. Process according to any one of claims 1 to 3, characterized in that the alcohol formed in the reaction is distilled together with the aromatic organic hydrocarbon.