HU189227B - Process for preparing basic oxime-ethers - Google Patents

Abstract

An improved process for the preparation of basic oxime ethers of 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 form 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 general Formula II <IMAGE> with a compound of general Formula III <IMAGE> (where Hal is a halogen atom) or an acid addition salt thereof in a mixture of water and a water- miscible organic solvent, in the presence of an alkali metal hydroxide and a phase transfer catalyst of the same formula as general Formula I or III.

Description

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

More particularly process (I) of basic oxime ethers of the general formula (R is optionally substituted with one to three halogen atoms and / or substituted C 1-4 lower alkoxy group wherein; are R ¹ and R ² each signify hydrogen or together a bond; A is C 1 -C 4 alkylene, R ³ and R ⁴ are each hydrogen or C 1 -C 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 to form a heterocyclic ring containing a nitrogen heteroalum and optionally substituted with C 1-4 alkyl, phenyl or phenyl (C 1-4 alkyl) and n is 3,4,5,6 or 7) and acid addition salts thereof.

The compounds of formula (1) are known to be useful in medicine due to their antidepressant, antiparkinsonian and local anesthetic effects (Hungarian Patent No. 169,298). According to the cited patent, the compounds of formula I are, inter alia, the compounds of formulas II and III (wherein Hal is halogen and R, R ¹ , R ² , R ³ , R ⁴ and π are). 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 it is. water is the solvent.

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 organic solvents used as reaction media are flammable and explosive; the reaction temperature is relatively high (130 'C); 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 during the winter.

The latter drawback is illustrated by the fact that, among other things, 2- (E) -p-chlorophenylmethylene-1 - [(E) -3'-diisopropylaminopropoxyimino)] - cyclohexane is 169,298. Pat. In addition to the expected product, a considerable amount of material of unknown structure is obtained, the physicochemical parameters of which are significantly different from those of the desired compound. The UV spectrum of the two compounds in the spectrum, it was found that the value of the desired compound is 280 nm (ε = 17456.15), the unknown material X _{m <value:} 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 the present invention relates to the preparation of pharmacologically active new compounds and its patent purpose was to produce sufficient quantities of chemical substances for the chemical identification and pharmacological action of the new compounds. The object of the present invention is disclosed in U.S. Patent No. 169,298. 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) of basic oxime ethers of the general formula (wherein R is optionally substituted with one to three halogen atoms and / or substituted C 1-4 alkoxy group; R ¹ and R ² each signify hydrogen or together form a chemical bond, A 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 an additional oxygen or nitrogen heteroatom; and heterocyclic ring optionally substituted with (1-4C) alkyl, phenyl or phenyl (1-4C) alkyl and n is 3,4,5,6 or 7) and the acid addition salts thereof with one of the formula (II); an oxime of the general formula (wherein R, R ¹ , R ² and n are as defined above) and the general formula (III) by reacting a halogen compound (wherein Hal is halogen and A, R ³ and R ⁴ are as defined above) such that g is an oxime of formula (II) wherein R, R 1, R ² and n are above) and the halogen compound of formula III (wherein Hal, A, R ³ and R ⁴ are as defined above) or an acid addition salt thereof are carried out in a mixture of water and a water-miscible organic solvent in the presence of an alkali metal hydroxide. In this case, the compound of formula (I) thus obtained is converted into an acid addition salt in a known manner.

In our experiments, it has been found that when the reaction of the compound of formula (II) with the compound of formula (III) or its salt in the presence of an alkali metal hydroxide in an aqueous medium yields only the desired compound of general formula (I). The present invention is based on the discovery that when the reaction of an oxime of formula II with a haloalkylamine of formula II or an acid addition salt thereof is carried out with water and

Is carried out in the presence of water-miscible organic solvent 189,227 of ₉ which was an alkali metal hydroxide, in prior art processes drawbacks discussed above do not occur and excellent yields of high purity (I) compound are obtained. This is because the starting material of formula (III) and / or the final product of formula (1) are believed to act as phase transfer catalysts. They are represented by the general formula (IV) (wherein R ⁵ and R ⁶ are C 1 -C 4 alkyl or together with the adjacent nitrogen to which they are attached a 5- to 7-membered, optionally containing an additional oxygen or nitrogen heteroatom and optionally 1). -4 alkyl, phenyl or phenyl- (l -4 alkyl) group to form a substituted heterocyclic ring and R ⁷ is one of (a) or (b) a radical of formula wherein Hal, n, R R ¹ and

R ² is as defined above). We do not intend to limit our invention to the above theoretical explanation.

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

The 5- to 7-membered heterocyclic group formed by R ³ , R ⁴ and the adjacent nitrogen, optionally containing an additional oxygen or nitrogen heteroatom, is optionally substituted. morpholino, pyrrolidino, piperidino, piperazino, Ν-methylpiperazino, N-phenylpiperazino or N-benzylpiperazino, and the like. may.

n is preferably 4 or 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.).

The water-miscible organic solvent of the present invention is a water-miscible alcohol, ether, ketone, acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine, hexamethylphosphoric triamide or sulfolane. It is particularly advantageous to use dimethylsulfoxide, acetonitrile, tetrahydrofuran or dimethylformamide as the water-miscible solvent.

The alkali metal hydroxide may be lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide or potassium hydroxide, or a mixture of the latter.

In a preferred embodiment of the process, the compound of formula (III) is used in the form of an acid addition salt, preferably an addition salt with an inorganic acid, most preferably a hydrochloric acid salt.

The reaction may be carried out at a temperature of 40 to 80 ° C, preferably 50 to 60 ° C.

The reaction is carried out under the above conditions in a short period of time, 0.5 to 3 hours, with the preferred reaction time being 1 to 2 hours.

The role of the phase transfer catalyst of formula (IV) acts as a (III) in the starting material of the formula (R ⁷ is a group (a) of formula I or formula (I) final product of formula (R ⁷ is a radical of formula (b)) in.

The reaction mixture is worked up by simple methods known per se. Alternatively, the final product is extracted with a water-immiscible and alkali-inert organic solvent (e.g., aromatic hydrocarbons such as benzene, toluene or xylene), and the extract is washed to neutral and evaporated.

The compounds of formula (I) obtained are known to be converted into the acid addition salts by reaction with an appropriate acid in an inert solvent medium.

In a particularly preferred embodiment of the process of the present invention, 2 - [(E) -chlorophenylmethylene)] - 1 - [(E) - (3'-diisopropylaminopropoxy-imino)] - cyclohexane is prepared by: to react 2 - [(E) - (p-chlorophenylmethylene)] -cyclohexan-1-one (E) -oxime with 1-diisopropylamino-3-chloropropane hydrochloride. This process is preferably carried out in a mixture of water and dimethylsulfoxide, a mixture of sodium hydroxide and potassium hydroxide.

The process according to the invention has the advantage that it can be advantageously implemented under operating conditions (rcvid reaction time, relatively low temperature, simple isolation, elimination of complex and special fine vacuum distillation purification, absence of explosive and environmentally unfavorable reactions, use of aqueous media) and, by suppressing side reactions, provides very pure material in very good yield.

The following non-limiting Examples illustrate the invention without further limiting it.

Example 1

Preparation of 2- (E) -phenylmethylene-1- (E) - (4'-phenyl-piperidinyl-propoxy-imino) -cyclohexane

50 cm ^{3 of} water, 40 g of sodium hydroxide and 10 g of potassium hydroxide are added to the apparatus equipped with a stirrer. After complete dissolution, 20.1 g (0.1 mol)

Of 2- (E) -phenylmethylene-cyclohexan-1-one (E) -oxime in 30 cm <^{3> of} dimethyl sulfoxide followed by 32.75 g (0.105 mol) of N-phenyl-N '- (3-chloro) in several portions. -propyl) -piperazine dichlorohydrate is added. Meanwhile, the reaction temperature was maintained at 50-55 ° C for 1-2 hours. After a few hours at room temperature, the reaction mixture was poured into 150 g of ice water and extracted with benzene. After washing the benzene solution to neutral, evaporate.

.189 227

Yield: 33.09 g (82%)

Chlorohydrate m.p. 189.5-193.5 ° 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, 70.97; H, 7.98; Cl, 7.94; N, 9.46.

Example 2

Preparation of 2- (E) -phenylmethylene-1- (E) - (4'-methyl-piperazinyl-propoxyimino) -cycloheptane

30 cm ^{3 of} water, 20 g of sodium hydroxide and 10 g of potassium hydroxide are weighed into a mixing apparatus. After complete dissolution, a solution of 21.5 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime in 20 cm <^{3> of} dimethylsulfoxide is added. The system was then heated at 60 ° C for half an hour, then

N-methyl-N '- (3-chloropropyl) piperazine (18.55 g, 0.105 mol) was added and the mixture was stirred at 60 ° C for 2 hours. At room temperature, 150 g of ice water and 100 cm <^{3> of} benzene are poured into the mixture, the benzene solution is separated off, washed with water to neutral and depressurized in vacuo. Yield: 33.38 g (90.3%)

2- (E) -Butenedioate (1/2) M.p .: 204-208 ° C Analysis calculated for C ₃ H ₄₃ 0 ₉ N ₃ (601.71) calculated: C 61.88%; H: 6 N, 7.20% Found: C: 62.03% H: 7.20% N: 7.12%

UV: _λmax = 272 nm (ε = 1370)

Example 3

Preparation of 2- (E) - (m-chlorophenylmethylene) -1 - [(E) -4'-benzyl-piperazinyl-propoxyimino] -c-cycloheptane

Weigh 50 cm ^{3 of} water and 50 g of potassium hydroxide into a stirred apparatus. After complete dissolution, a solution of 24.97 g (0.1 mol) of 2 - [(E) - (m-chlorophenylmethylene)] - cycloheptan-1-one (E) -oxime in 25 cm <^{3> of} acetonitrile. After 1 hour of reaction at 60 ° C, 35.72 g (0.11 mol) of N-benzyl-N '- (3'-chloropropyl) -piperazine dichlorohydrate are added in small portions. After the addition was complete, the reaction was reacted at 60 for 2 hours. It is poured onto 100 g of crushed ice and extracted with dichloroethane, and the organic phase is then stripped of solvent.

Yield: 36 g (79.8%).

2- (E) -butenedioate (1/2): m.p. 196-199 ° C Analysis calculated for C ₃₅ H ₄₂ ClN ₃ O ₉ (684.20): C, 61.44; H, 6 , 18% Cl: 5.18% N: 6.14%; Found: C, 61.58; H, 6.34; Cl, 5.21; N, 6.24.

uv: λ _{η η} = 274 nm (e = 13,700)

Example 4

Preparation of 2- (E) -phenylmethylene-1 - [(E) - (4'-benzyl-piperazinylethoxyimino) -cycloheptane

Add 50 ^cm3 of water and 50 g of sodium hydroxide are stirred apparatus. After complete dissolution, a solution of 21.53 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime in 25 cm ^{3 of} tetrahydrofuran is added, followed by 34.19 g (0, N-BenzylN '- (2-chloroethyl) piperazine dichlorohydrate (11 mol) was added and stirred at 50 ° C for 2 hours. The reaction mixture was poured onto 200 g of crushed ice and extracted with 100 x 2 x 50 cm ^{3 of} benzene, and the benzene solution was de-solvented.

Yield: 40.4 g (97%).

Dichlorohydrate, m.p. 206-208 ° C Analysis calculated for C ₂₇ H ₃₆ ClN ₃ O (489.62): C, 66.23; H, 7.43; Cl, 14.56; N, 8.58. %;

Found: C, 65.95; H, 7.49; Cl, 14.27% N:

8.42%.

UV:? _max = 262 nm (ε = 17012)

Example 5

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

To the apparatus equipped with a stirrer was added cm ^{3 of} water, 40 g of potassium hydroxide and 10 g of sodium hydroxide. After complete dissolution, a solution of 23.57 g (0.1 mol) of 2 - [(E) - (p-chlorophenylmethylene)] - cyclohexanone-one (E) -oxime in 20 cm <^{3> of} dimethylformamide was added. 18.55 g (0.105 mol) of N-methyl-N '- (3-chloropropyl) piperazine are added and the mixture is reacted for 2 hours at 70 ° C. It is then poured onto 150 g of crushed ice and quenched with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and de-solvented. Yield: 36.5 g (92.7%) • N - (E) -butenedioate (1/2): m.p. 196-199 ° C Analysis for C ₂₉ H ₃₈ ClN ₃ O ₉ (608.1) Found: C, 57.28; H, 6.29; Cl, 5.83; N, 6.91. Found: C, 57.35; H, 6.21; Cl, 5.97; N, 6.81.

uv: _λmaK = 278 nm (ε = _16,507 )

Example 6

Preparation of 2 - [(E) - (o-chlorophenylmethylene)] - 1 - {(E) - (4'-benzylpiperazinylpropoxyimino) - J -cyclohexane

From 23.57 g (0.1 mol) of 2 - [(E) - (o-chlorophenylmethylene) cyclohexan-1-one (E) -oxime, 35.72 g (0.11 mol) of N-benzyl Starting with -N '- (3-chloropropyl) piperazine dichlorohydrate, the procedure of Example 4 gave 39.02 g (86.3%) of the title compound. 2- (E) -butenedioate (1/2): m.p. 196-201 ° C.

Analysis calculated for C ₃₅ H ₄₂ ClN ₃ O ₄ (684.2): C, 61.44; H, 6.15; Cl, 5.19; N, 6.14; Found: C, 61.37; H, 6.35; Cl, 5.3; N, 5.97.

uv: _λmax = 269 nm (ε = _11,573 )

Example 7

3 - [(E) - (2 ', 4'-Dichlorophenylmethylene)] ~ 1 ~ [(E) -4' ~

Benzyl-piperazinyl-propoxyimino) -J-cyclohexane

27.02 g (0.1 mol) of 2 - [(E) - (2 ', 4'-dichlorophenylmethylene)] - cyclohexan-1-one (E) oxime and 35.72 g (0 Starting from N-benzyl-N '- (3-chloropropyl) piperazine dichlorohydrate (11 mol), otherwise, Example 1 gave 39.56 g (81.3%) of the title compound.

2- (E) -butenedioate (1/2): mp 198.5-201.5 ° C.

189,227

Analysis calculated for C ₃₅ H ₄₁ Cl ₂ N ₃ O ₉ (718.65): C, 58.5; H, 5.75; Cl, 9.86; N, 5.84. Found: C, 58.7; H, 5.75; Cl, 9.72; N, 5.83. uv: k _max = 273 nm (ε = 15,409)

Example 8

Preparation of 2-f (E) - (m-chlorophenylmethylene) -J - 1 - [(E) -4'-benzylpiperazinyl-ethoxyimino)] - cyclohexane

23.57 g (0.1 mol) of 2 - [(E) - (m-chlorophenylmethylene)] cyclohexan-1-one (E) -oxime and 34.2 g (0.11 mol) of N starting from benzyl N '- (2-chloroethyl) piperazine dichlorohydrate, otherwise according to Example 3

40.62 g (92.7%) of the title compound are obtained.

2- (E) -butenedioate (1/2): mp 196.5-199.5 ° C Analysis calculated for C ₃₄ H _{4 O} ClN ₃ O ₄ (670.18): C, 60.94. % H: 6.02% Cl: 5.3% N: 6.27%; Found: C, 60.1; H, 6.01; Cl, 5.37; N, 6.12. uv: Amx ⁼ 274 nm (ε = 15,246)

Example 9

Preparation of 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 1-chloroethane, otherwise, Example 2 gave 28.46 g (94.7%) of the title compound.

2- (E) -butenedioate (1/1): m.p. 120-123 ° C Analysis calculated for C ₂₃ H ₃₂ N ₂ O ₅ (416.51): Calculated: 66.32% H: 7.75. % N: 6.73%; Found: C, 66.48; H, 7.95; N, 6.70.

uv: λ _max = 262 nm (ε = 17,595)

Example 10

Preparation of 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, otherwise according to Example 2, 26.9 g (93.9%) of the title compound are obtained.

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, 65.98; H, 7.60; N, 7.00.

uv: ^ _maK = 273 nm (ε = _13,475 ) ll. example

Preparation of 2- (E) -phenylmethylene-1 - [(E) - (2'-diisopropylamino-ethoxyimino)] - cyclooctane

22.93 g (0.1 mole) of 2- (E) -phenylmethylene-cyclooctane-on-one (E) -oxime and 22.02 g (0.11 mole) of 1-diisopropylamino-2-chloro- starting from ethane, otherwise according to Example 4, 31.62 g (88.7%) of the title compound are obtained.

The hydrochloride melts at 158-161 ° C.

Analysis for C ₂₃ H ₃₇ ClN ₂ O (393.0):

Calculated: C: 70.29% H: 9.47 ° ₀ Cl: 9.02% N: 7.13 ',,; Found: C, 70.44; H, 9.5; Cl, 8.98; N, 7.23.

uv: λ _ηωι = 276 nm (ε = _14,170 )

Example 12

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

22.93 g (0.1 mol) of 2- (E) -phenylmethylene-cyclooctane-1-one (E) -oxime and 17.39 g (0.1 mol) of 1-dimethylamino-3-chloropropane- Starting from the hydrochloride, in the same manner as in Example 1, 27.35 g (91%) of the title compound are obtained.

2- (E) -butenedioate (1/1): mp 136-138.5 ° C

Analysis calculated for C ₂₃ H ₃₂ N ₂ O ₅ (416.52): C, 66.32; H, 7.75; N, 6.73. Found: C, 66.74; H, 7.96; N, 6.61.

uv: λ, _{) Μ} = 276 nm (ε = 14,395)

Example 13

Preparation of 2- (E) -phenylmethylene-1 - [(E) - (2'-dimethylaminoethoxyimino)] - cycloheptane

21.53 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-1-one (E) -oxime and 18.07 g (0.105 mol) of 1-diethylamino-2-chloro- Starting with ethane hydrochloride as in Example 3, 28.99 g (92.2%) of the title compound are obtained.

2- (N) -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, 8.06; N, 6.46.

uv: The _mas = 264 nm (ε = 16395)

Example 14

Preparation of 2- (E) -phenylmethylene-1- (E) - (2'-di: opropylaminoethoxyimino)] -cyclohexane

Starting from 20.13 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexan-1-one (E) -oxime and 22.02 g (0.11 mol) of 1-diisopropylamino-2-chloroethane hydrochloride otherwise, Example 1 afforded 30.99 g (94.3%) of the title compound. 2- (E) -butenedioate (1/1) mp 103-105 ° C. Analysis: Calculated for C _{2 S} H ₃₆ N ₂ O _S (444.58): C, 67.54; H, 8.16; N, 6.30.

Found: C, 67.54; H, 8.34; N, 6.34.

UV:? _max = 275 nm (ε = 17304).

Example 15

Preparation of 2-benzyl-1 - [(E) - (2'-dimethylaminoethoxyimino)] -cycloheptane

Starting from 21.63 g (0.1 mol) of 2-benzyl-cycloheptan-1-one (E) oxime and 16.84 g (0.11 mol) of 2-dimethylamino-1-chloroethane hydrochloride, otherwise

Example 1 gave 26.17 g (90.7%) of the title compound.

2- (E) -butenedioate (1/1) m.p. 121-124 ° C. Analysis calculated for C ₂₂ H ₃₂ N ₂ O ₅ (404.51): C, 65.32; H, 7.97; N, 6.93; Found: C, 65.77; H, 8.04; N, 7.11.

189,227

Example 16

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

23.57 g (0.1 mol) of 2 - [(E) - (p-chlorophenylmethylene)] cyclohexane-1-one (E) oxime and 12.24 g (0.105 mol) of 1-dimethyl Starting from -amino-2-chloroethane, otherwise as in Example 2, 28.97 g (94.4%) of the title compound are obtained.

2- (E) -butenedioate (1/1) mp 168.5 at 170.5 ° C. Calcd for C ₂ H ₂₇ C1N ₂ O ₅ (422.92) Analysis: C: 59.64% H: 6.44% Cl: 8.38% N: 6.62%; Found: C, 59.97; H, 6.74; Cl, 8.28; N, 6.46.

u.v .: kux = 275 nm (ε = 19,292)

Example 20

Preparation of 2- (E) -phenylmethylene [(E) -2'-diethylaminoethoxy-imino] -cyclopentane

Starting from 18.7 g (0.1 mol) of 2- (E) -phenylmethylene-cyclopentan-1-one (E) -oxime and 14.9 g (0.1 mol) of 1-diethylamino-2-chloroethane otherwise, Example 2 gave 29.48 g (82.5%) of the title compound.

2- (E) -butenedioate (1/1) melts at 123-124 ° C. Analysis calculated for C ₂₂ H ₃₀ N ₂ O ₅ (402.50): C, 65.65; H, 7.51; N, 6.96. Found: C, 65.50; H, 7.42; N, 6.95.

uv: kax ⁼ 304 nm (ε = 25,800)

Example 17

Preparation of 2 - [(E) - (p-Chlorophenylmethylene)] - [(E) - (3'-diisopropylaminopropoxyimino) -? - cyclohexane

23.57 g (0.1 mol) of 2 - [(E) - (p-chlorophenylmethylene)] cyclohexanone-one (E) -oxime and 23.55 g (0.11 mol) of 1-diisopropyl starting from -amino-3-chloropropane hydrochloride, otherwise as in Example 1

35.63 g (94.5%) of the title compound are obtained.

2- (E) -butenedioate (1/1) m.p. 87-89.5 ° C. Analysis calculated for C ₂₆ H ₃₇ CIN ₂ O ₅ (493.06): C, 63.34; H, 7.56; Cl, 7.19; N, 5.68. Found: C, 63.30; H, 7.54; Cl, 7.13; N, 5.60.

uv: ka. = ^{280 nm} ( ^ε = 17,456.15)

Example 18

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

20.13 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexanen-one (E) -oxime and 23.55 g (0.11 mol) of 1-diisopropylamino-3-chloro- starting from propane hydrochloride and proceeding as in Example 1.

31.99 g (93.4%) of the title compound are obtained.

2- (E) -butenedioate (1/1) melts at 128.5-113.5 ° C. Analysis calculated for C ₂₆ H _{3 S} N ₂ O ₅ (458.61): C, 68.09; H, 8.35; N, 6.10; Found: C, 68.28; H, 8.35; N, 6.28.

^uv - ^: k, <= ^{275 nm} { ^ε =

Example 19

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

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 starting from chloroethane hydrochloride, for example, Example 1. Yield: 32.58 g (95.1%).

2- (E) -butenedioate (1/1) melts at 117-120 ° C. Calcd for C ₂₆ H ₃₈ N O _{2 S} (458.6) calculated: C 68.09% H 8.35% N: 6.11%; Found: C, 68.33; H, 8.46; N, 6.13.

uv: ⁼ 258 nm (ε = 11,182)

Example 21

Preparation of 2- (E) -phenylmethylene-1 - [(E) -2'-diethylaminoethoxyimino] -cyclohexane

20.13 g (0.1 mol) of 2- (E) -phenylmethylene-1-one (E) oxime and 18.93 g (0.11 mol) of 1-diethylamino-2-chloroethane hydrochloride start and proceed as in Example 1.

Yield: 32.28 g (77.5%).

2- (E) -butenedioate (1/1) m.p. 111-112 ° C. Analysis calculated for C ₂₃ H ₃₂ N ₂ O ₅ (416.53): C, 66.33; H, 7.74; N, 6.72. Found: C, 65.92; H, 7.60; N, 6.70.

u.v.: ka, ~ 275 nm (ε = 15,300)

Example 22

Preparation of 2- (E) -phenylmethylene-1 - [(E) -2'-dimethylaminoethoxyimino] -cyclopentane

Starting from 18.7 g (0.1 mol) of 2- (E) -ferylmethylene-cyclopentan-1-one (E) oxime and 16.07 g (0.105 mol) of 1-dimethylamino-2-chloroethane hydrochloride and the like in Example 1. Yield: 26.96 g (77.0%)

2- (E) -butenedioate (1/1) mp 126-128 ° C. Analysis calculated for C ₂₀ H ₂₆ N ₂ O ₅ (374.44): C, 64.18; H, 7.00; N, 7.47. Found: C, 64.00; H, 6.87; N, 7.44.

uv: λ _ιιιιιχ = 303 nm (ε = 23 587)

Example 23

Preparation of 2- (E) -phenylmethylene-1 - [(E) -2'-dimethylaminoethoxyimino] -cyclohexane

20.13 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexanen-one (E) -oxime and 11.8 g (0.11 mol) of 1-dimethylamino-2-chloroethane are obtained. who and others a

Example 2 was followed.

Yield: 30.02 g (77.3%).

2- (E) -butenedioate (1/1) m.p. 141-143 ° C. Analysis calculated for C ₂₁ H ₂₈ N ₂ O ₅ (388.47): C, 64.92; H, 7.27; N, 7.21; Found: C, 64.71; H, 7.11; N, 7.20.

uv: kax = 275 nm (ε = 15,927)

-6I

189,227

Example 24

Preparation of 2 - [(E) - (p-chlorophenylmethylene)] - 1 - [(E) -3'-dimethylaminopropoxyimino] -cycloheptane

24.93 g (0.1 mol) of 2- (E) -p-chlorophenylmethylene) cycloheptane) -1-one (E) oxymol and 13.3 g (0.11 mol) of 1-dimethyl Starting from amino-3-chloropropane, the procedure of Example 2 gave 33.15 g (73.5%) of the title compound.

2- (E) -butenedioate (1/1) melts at 160-161 ° C. Analysis calculated for C ₂₃ H ₃₁ ClN ₂ O ₅ (450.97): C, 61.22; H, 6.94; N, 6.22; Found: C, 61.12; H, 6.73; N, 6.20.

,: uv _.lambda.max = 268 nm (ε = 19759)

Example 28

Preparation of 2 - [(E-Phenylmethylene) -1- (E) - (2'-aminoethoxyimino) cyclohexane

20.13 g (0.1 mol) of 2 - [(E) -phenylmethylene] -1-one (E) oxime and 17.65 g (0.11 mol) of I-amino-2-chloroethane hydrobromide Starting, in the same manner as in Example 1, 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; 33% N, 9.27% Found: C, 67.24% H, 7.19% N, 9.31%

uv: λ _ηΜ = 275 nm (ε = 18,000)

Example 25

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

26.73 g (0.1 mol) of 2 - [(E) - (m-methoxyphenylmethylene)] - 1-one (E) oxime and 35.72 g (0.11 mol) of N- starting from benzyl-N '- (3'-chloropropyl) piperazine dihydrochloride, in the same way as in Example 1.

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 ₀ (679.78): C, 63.61; H, 6 N, 6.18; C, 63.79; H, 6.89; N, 6.12.

uv: ⁼ 272 nm (ε = 14,820)

Example 26

Preparation of 2 - [(E) -phenylmethylene] -1- (3'-morpholino-propoxyimino) -cyclohexane

Starting from 20.13 g (0.1 mol) of 2- (E) -phenylmethylene-1-one (E) oxime and 19.39 g (0.1 mol) of 1-chloro-3-morpholinopropane hydrochloride, Example 1 gave 25.95 g (79%) of the title compound.

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: \ nax ^{= 276 nm} ( ^ε ~ 15,400)

Example 27

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

- (4'-Methyl-piperazinyl-propoxyimino)] -cyclohexane

29.13 g (0.1 mol) of 2 - [(E) - (3 ', 4', 5'-trimethoxyphenymethylene)] - 1-one- (E) -oxime and 23.57 g (0.105 mol) ) Starting from N-methyl-N '- (3-chloropropyl) piperazine and proceeding as in Example 1.

Yield: 33.5 g (77.7%)

2- (E) -butenedioate (1/2) m.p.

Analysis calculated for C ₃₂ H ₄₅ N ₃ O ₁₂ (663.70): C, 57.91; H, 6.83; N, 6.33. Found: C, 58.30; H, 6; 99% N: 6.52%

uv: k _ax = 294 nm (ε = 20,500)

Claims (7)

A process for preparing basic oximeters of formula (I) wherein R is phenyl optionally substituted with one to three halogens and / or C 1-4 alkoxy; R 1 and R ² are each hydrogen or taken together to form a bond; 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 an additional oxygen or nitrogen heteroatom; forming a heterocyclic ring containing from 1 to 4 carbon atoms, optionally substituted with C 1 -C 4 alkyl, phenyl or phenyl (C 1 -C 4 alkyl), and n is 3,4,5,6 or 7); oxime of formula (wherein R, ^R!, R ² and n are as defined above) and (III) a halo compound of formula let (wherein Hal is halogen and A, R ³ and R ⁴ are as defined above), wherein the oxime of formula (II) wherein R, R ¹ , R ² and n are as defined above ) and the halogen compound of formula III (wherein Hal, A, R ³ and R ⁴ are as defined above) or an acid addition salt thereof in a mixture of water and a water-miscible organic solvent in the presence of an alkali metal hydroxide. In this case, the compound of formula (I) thus obtained is converted into the acid addition salt in a known manner. 2. The process according to claim 1, wherein the water-miscible organic solvent is dimethylsulfoxide, acetonitrile, tetrahydrofuran or dimethylformamide. 3. The process according to any one of claims 1 to 3, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide or a mixture thereof. 4. Process according to any one of claims 1 to 3, characterized in that the hydrogen compound of formula (III) is used in the form of its inorganic acid salt, preferably its hydrochloric acid salt. 5. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at 40-80 'C, preferably 50-60' C. 6. The method of any one of claims 1 to 7 189,227, characterized in that the reaction is carried out for 0.5 to 3 hours, preferably 1 to 2 hours. A process according to any one of claims 16 to prepare 2 - [(E) -p-chlorophenylmethylene)] - 1 - [(E) - (3'-diisopropylaminopropoxyimino)] - cyclohexane, characterized in that 2 - [(E) - (p-chlorophenylmethylene)] - cyclohexane-1-one (E) -oxime in a mixture of water and dimethylsulfoxide, in the presence of sodium hydroxide or potassium hydroxide, It reacted with ^{3-amino-5-chloro-propane} hydrochloride.