DE3404424A1 - METHOD FOR PRODUCING BASIC OXIMAETHERS - Google Patents

Description

DR. STEPHAN G. BESZiDES PATENT ADVOCATE

VNR: 101265

AUTHORIZED REPRESENTATIVE AT THE EUROPEAN PATENT OFFICE

PROFESSIONAL REPRESENTATIVE ALSO BEFORE THE EUROPEAN PATENT OFFICE

DACHAU NEAR MUNICH

BOX 1168

MDNCHENER STRASSE 8OA

Federal Republic of Germany

TELEPHONE: O ACH AU 081 31/4371 TELEX: 527537 bepat d

Postal checking account Munich (BLZ 700 100 80)

Account No. 1 368 71-801 Bank account No. 906 370 at the Sparkasse Dachau

(Sort code 700 515 40)

(VIA Bayerische Landesbank

Girozentrale. Munich)

P 1 893

Claims and Description

for patent application

EGXT GIOGIJZ ^ ViGI ^ SZi

Bud ap e s t, ling ar n

concerning

Process for the production of basic oxime ethers

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

The subject of the invention is a method z ^ x ' Production of basic oxime ethers of the general formula I.

_R 3 - (CH ₉ ) C = N - 0 - A - N ^ (I)

(wherein

R is optionally through 1-3 halogen atom (s) and / or lower alkoxy group (s) represents substituted phenyl group;

1 2
R and R each represent hydrogen or together form a valence bond; A represents lower alkylene;
R ^ and R each represent hydrogen or lower alkyl

stand or together with the nitrogen atom to which they are attached, one 5-8-membered heterocyclic ring, which optionally contains a further oxygen or nitrogen atom and / or by lower alkyl, phenyl der Phenyl-lower alkyl may be substituted; and

η stands for 3, 4-, 5, 6 or 7) and acid addition salts thereof.

"": ..:.; ·; '- "." T 3A04424

-β-

It is known that the compounds of general formula I are antidepressant, antiparkinsonian and exert local anesthetic effects (Hungarian patent specification No. 169 298). According to this patent specification the compounds of the general formula I can inter alia. by converting compounds of the general formulas II and III

ι Q V.VUO / _ \ ja ■ '' uti

(II)

r
Shark - A - N (III)

(where Hal stands for halogen and R, R ¹ , R ² , R ^, R ^, A and η have the above meaning) in an inert solvent, in the presence of a basic condensing agent. In the examples of the patent, the inert solvents used are exclusively organic solvents (toluene,

Ethanol, benzene or xylene) and as a basic condensing agent Sodium hydride, sodium amide or metallic sodium are used. It will continue to be in the Description without experimental support mentions that alkali metal

hydroxides can be used; in this case water plays the role of the solvent. In the According to Hungarian patent specification 169 298, the use of alkali metals is an alcoholic medium suggested.

The method disclosed in the cited patent specification is associated with the following disadvantages, especially when carried out on a large scale during operation:
- The haloalkylamines of the general formula III can only be used in the form of the base; the free bases of the general formula III are unstable substances inclined to dimerization or polymerization;

- The level of exploitation of the facilities is unfavorable during implementation;

- the reaction time is long (12-16 hours);

- the end product is isolated using complicated methods (decomposition of sodium hydride or sodium amide, acidic or alkaline extractions or compressing, etc.);

- the purification is carried out by high vacuum distillation using complex and special Facilities carried out;

- The hydrogen gas developed in the reaction is explosive and the ammonia formed is environmentally unfriendly;

- in some cases isomerization occurs.

The latter disadvantage can also be demonstrated by the fact that during the manufacture of the 2-ZrE) - (p-chloro-phenylmethylene17-1- / CE) - (3'-diisopropylamino-propoxyimino27-cyclohexane after the hungarian

340U24

In patent specification No. 169 298, a substance of unknown structure is formed in a considerable amount in addition to the desired compound. The physicochemical parameters of this by-product are substantially different from the corresponding values of the target compound. An analysis of the UV spectrum shows that the Jl 'value of the target compound is 280 nm (€ = 174-56.15), whereas this value of the unknown substance * _mQ v ^{: 2} ^ 3 ¹ ^ ¹ Ct = 124-5) amounts to.

This big difference confirms the fact that there was an undesirable side reaction during the conversion (Isomerization) took place.

Hungarian patent specification No. 169 298 relates to a process for the preparation of pharmaceutical effective new compounds. The aim of this invention was to prepare the new compounds in one for Perform chemical identification and pharmacological Trials sufficient amount. On the other hand, the aim of the present invention is to provide a process for the production of these known compounds, which also in operation in large Scale is economically feasible and the requirements of environmental protection, energy saving and is economical.

The invention relates to a process for the preparation of basic oxime ethers of the general formula I.
(wherein
R denotes a phenyl group which is optionally substituted by 1-3 halogen atom (s) and / or lower alkoxy group (s);

ι P
R and R each stand for hydrogen or together

form a valence bond; A represents lower alkylene;

R ^ and R ^ each represent hydrogen or lower alkyl or together with the nitrogen atom which they are bound, a 5-8-

-membered heterocyclic ring, which optionally another oxygen or nitrogen atom and / or by lower alkyl, phenyl or phenyl -lower alkyl may be substituted; and

η stands for $, 4, 5 _r 6 or 7)

and pharmaceutically acceptable acid addition salts thereof by reacting an oxime of the general Formula II with a halogen compound of the general

Formula III (in which Hal stands for halogen and R, R ¹ , R ² ,

3 4
R, R, A and η have the above meaning), characterized in that the reaction of the oxime of the general formula II and the halogen compound of the general formula III or an acid addition salt

of it in the presence of a lower one

Alkali metal alcoholate and an aromatic organic hydrocarbon carries out and if desired, the compound of the general formula I obtained in this way by known methods in one Acid addition salt transferred.

It has been found that if the reaction of the oxime of the general formula II and the halogen compound of the general formula III or an acid addition salt thereof in the presence

of an alkali alcoholate and an aromatic organic hydrocarbon carries out the reaction within a short time with excellent

Yield expires and a very pure, isomer-free product is obtained.

The term "lower alkoxy" used in the specification relates to Geraa _A ettige or branched alkoxy groups having 1-4 carbon atoms (eg, methoxy, Athoxy, isopropoxy n-propoxy etc.). The term "halogen ¹ 'includes the fluorine, chlorine, bromine and iodine atoms. Under the term" lower alkylene "are straight-chain or branched alkylene groups with 2-4 carbon atoms to"
understand (e.g. ethylene, trimethylene or 1-methylethylene, etc.). The term "lower alkyl" refers to straight or branched chain alkyl groups having 1-4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, etc.).

X L \.

The groups Ir and R can be linked to the neighboring Nitrogen atom to which they are attached form a 5-8- membered heterocyclic ring, which optionally contain another oxygen or nitrogen atom and / or by lower alkyl, phenyl or Phenyl-lower-alkyl can be substituted. Beneficial Representatives of these heterocyclic rings are e.g. the morpholino, pyrrolidino, piperidino, N-methyl-piperazino, N-phenyl-piperazino and N-benzylpiperazinc groups, etc. η advantageously stands for 4 or 5

The acid addition salts of the compounds of general formula I can be mixed with pharmaceutically suitable salts formed from inorganic or organic acids (e.g. hydrochlorides, hydrobromides, sulfates, maleates, Fumarates, acetates, lactates, etc.).

according to the inventive method can as Alkalimetallalkohoiat advantageously sodium methylate, sodium ethylate, potassium ethylate, potassium ethylate or

Kaliuir.-tert. butylate can be used. As more aromatic organic hydrocarbon can advantageously be used benzene, toluene, xylene or a mixture thereof will.

According to a particularly advantageous embodiment of the process according to the invention, the reaction is the compounds of the general formulas II and III in the presence of sodium methylate and toluene,

Xylene or benzene carried out.

The reaction is advantageously carried out with heating at the boiling point of the reaction mixture. It is advantageous to proceed in such a way that the lower alkanol formed in the course of the reaction together with distilled off the aromatic organic solvent from the reaction mixture. The reaction is running

within a very short time - about 1-2 hours. The starting material of the general formula III can also in the form of an acid addition salt, advantageously in the form of one formed with an inorganic acid Addition salt, can conveniently be used as the hydrochloride.

The reaction mixture is worked up by methods known per se. According to one method will the reaction mixture poured into water, washed and evaporated. According to an alternative method, the Compound of general formula I in Forrr. an acid addition salt isolated.

The salt formation can be carried out in a manner known per se by reaction with the appropriate acid in an inert Solvent can be realized as a medium.

According to an advantageous embodiment of the method according to the invention, the following can be used

340U24

Connections are made:

2- / Te) -Pheny Imethyleß7-1- / IE) - (3 '-diisopropylamino- propoxyimino,) 7-cyclohexane;

2 - / '(E) - (p-chloro-phenylmethylene) .7-l-ZTE) - (3 ⁱ -diisopropylamino-propoxyimino) -7-cyclohexane; 2-Benzal-1- (2'-diisopropylamino-ethoxyimino) -cycloheptane

The advantages of the method according to the invention can be summarized as follows: the method can also be economical in large-scale operation be carried out (short reaction time; simple isolation; no purification by high vacuum distillation with complicated and special facilities; Elimination of the explosive reactions), the side reactions are pushed back, a highly pure product is obtained with excellent yields.

Further details of the invention Process can be found in the following examples, without the scope of protection on these examples to restrict.

example 1

Preparation of the 2-Z {E) - (2>, ^ -'-dichloro-phenylmethylene17-1- / tE) - ( ^z l- ⁱ -benzyl-piperazinyl-propoxyiminoX7-cyclohexane

150 ml anhydrous toluene, 5 »4 S (0.01 mol) Sodium methylate and 27.02 g (0.1 mol) 2 - / (E) - (2 », 4'- -Dichlorophenylmethylene) / -cyclohexan-l-one- (E) -oxime are weighed into a flask equipped with a stirrer. About 30 ml of the reaction mixture a methanol-toluene mixture was distilled off, whereupon a solution of 27.7 g with heating to boiling

(0.11 mol) of N-benzyl-N '- (5-chloropropyl) piperazine and 50 ml of toluene is added. The reaction mixture is left to stand for 1-2 hours, poured into 150 ml of ice-cold water, the toluene solution is washed neutral and concentrated under reduced pressure. A- ^1,0 A g of the compound mentioned in the title are obtained, yield 86.2 %.

The 2- (E) -butenedioate (1/2) melts at 197-200.5 G ⁰ .

Analysis: Calculated for the formula C ₅₅ H ^ ₁ Cl ₂ N ₅ Og (718.65): C 58.5 # H 5.75 % Cl 9.86 K> N 5.84 # found: C 58.4 $ H 5.69 % Cl 9.79 % N 5.87 % UV .: l _max = 273 nm (€ = 154-09)

Example 2

Production of the 2- / £ E) - (m-chloro-phenylmethylene) 7- -l- / f £ E) - (4 -'- Benzylpiperazinyl - ethoxyimino) 7- -cyclohexane

23.57 g (0.1 mol) 2 - / "(E) - (m-chloro-phenylmethylene) / -cyclohexan-l-one- (E) -oxime, 150 ml of xylene and 18.9 g (0.35 mol) of sodium methylate are in a with a The flask provided with a stirrer is weighed. From the reaction mixture are stirred at atmospheric pressure 30 ml of a xylene-methanol mixture was distilled off. the The temperature of the reaction mixture is reduced below the boiling point and 34.2 g (0.11 mol) of N-benzyl-N »- - (2-chloroethyl) piperazine dihydrochloride are added. The reaction mixture is with removal of 50 ml of solvent heated for a few hours, after which the mixture was cooled to 20 C °, in Poured 200 ml of ice-cold water, the xylene phase separated, washed neutral with water and taken under

is concentrated under reduced pressure. 38.25 g of the compound mentioned in the title are obtained, yield 87.3 # · The 2- (E) -butenedioate (1/2) melts at 197-199.5 G ⁰ . Analysis: based on the formula C ^ H ^ qCIN ^ O ^ (670.2)

calculated: C 60.94 % H 6.02 % Cl 5.29 # N 6.27 % found: C 61.04 % H 6.13 % Gl 5.25 % N 6.31 % = 274 nm (£ = 15246)

IUoLX

Example 3

Preparation of 2- (E) -phenylmethylene-l- / rE) - (4'- -phenyl-piperazinyl-propoxyimino} / -cyclohexane

The procedure is as in Example 1, with the difference that 20.1 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexan-l-one- (E) -oxime and 25.0 g are used as starting material (0.105 moles) N-phenyl-N '- (3-chloropropyl) piperazine used. 35.19 g of the compound mentioned in the title are obtained, yield 87.2 %. The hydrochloride melts at 190-194 ° C. Analysis: calculated on the formula C ₂₆ H ^ Cl N ₅ 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

Production of the 2-Z (E) - (o-chloro-phenylmethylene27- -l- / lE) - (4'-Benzylpiperazinyl-propoxyimino) / - -cyclohexane

The procedure is as in Example 2, with the difference that the starting material is 23.57 g (0.1 mol) 2-ZlE) - (o-chloro-phenylmethylenel7-cyclohexan-l-one- (E) - -oxime and 35.72 g (0.11 mol) of N-benzyl-N '- (3-chloropropyl) -piperazine dihydrochloride used. 37.71 g of the compound mentioned in the title are obtained,

Yield 83.4 #.

The 2- (E) -butenedioate (1/2) melts at 197-201 C ⁰ .

Analysis: based on the formula C ^ H ^ CIN ^ (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: 0 = 269 nm (£ = 11573)

IIlcLüv

Example 5

Preparation of the 2-Z £ E) -phenylmethylene / -l- ₁ ZlE) - - (4 -'-benzyl-piperazinylethoxyimino) / - cycloheptane

The procedure is as in Example 1, with the difference that 21.53 g (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-l-one- (E) -oxime and 26.16 g ( 0.11 mol) of N-benzyl-N '- (2-chloroethyl) piperazine is used. 38.8 g of the compound mentioned in the title are obtained, yield 93.2 %. The dihydrochloride melts at 206-209 C ⁰ .

Analysis: calculated for the formula C ₂₇ H ₅₆ ClN ₅ O (4-89.62): C 66.23 % H 7.4-3 % Cl 14-, 56 % N 8.58 % found: C 66.12 % H 7.15 % Cl 14-, 62 % N 8.61 %

= ^{262 nm} (£ = 17012)

Example 6

Production of the 2-Z (E) -Phenylmethylene7-l - / ^ E) - - (3'-Diisopropylaminopropoxyimino ^ 7-cyclohexane

Proceed as in Example 1, with the

The difference is that 20.13 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexan-l-one- (E) -oxime and 19.53 g (0.11 mol) of l-diisopropylamino- 3-chloro-propane is used. 33.05 g of the compound mentioned in the title are obtained. Yield 96.5 # · The 2- (E) -butenedioate (l / l) melts at 130-132 C ⁰ .

340U24 - / β-

Analysis: on the formula C. = 26 ^H. 38 2 5 C4 58 , 61 expected: C. 68 .09 $> H 8th XC. Oil N 6th , 10 found: C. 67 , 95 % H 8th , 4-2 % N 6th , 03 ^{υ ν :} * max = 275 nm (p ⁾ Example 7

Production of the 2- ^ CE) - (p-chloro-phenylmethylene ^ 7- -l - ^ (E) - (3'-diisopropylamino-propoxyimino} 7- -cyclohexane

The procedure is as in Example 1, with the difference that 23.6 g (0.1 mol) of 2- ^ E) - (p-chloro-phenyl-methylenl7-cyclohexan-l-one- (E) - -oxime and 19.54- g (0.11 mol) of 1-diisopropylamino-3-chloro-propane are used. 37.14% of the compound mentioned in the title are obtained, yield 98.5 # ) -Butenedioate (l / l) melts at 87-89.5 ° C. Analysis: based on the formula C ₂₆ H ₅₇ ClN ₂ O ₅ (4-93.06): C 63.34 % H 7.56 $ Cl 7.19 % N 5.68 % found: C 63.22 % H 7.4-9 # Cl 7.18 % N 5.72 % UV: α _av = 280 nm (C-174-56)

Max

Example 8

Preparation of 2- ^ Z) -Phenylmethylene7-1- / l2 ^> -diisopropylamino-athoxyimino ^ Z-cycloheptane

The procedure is as in Example 2, with the difference that the starting material is 21.53 g (0.1 mol) 2- (Z) -Phenylmethylene-cycloheptan-l-one- (E) -oxime and 22.02 g (0.11 mol) l-dimethylamino-2-chloroethane hydrochloride used. It will be 31.3 g in the title obtained compound, yield 91.4- #.

The 2- (E) -butenedioate (l / l) melts at 117-120 C ⁰ .

Analysis: for the formula ^C 26 ^H 38 ^N 2 ° 5

calculated: C 68.09 # H 8.35 % N 6.11

Found: C 67.92 % H 8.4-2 % N 6.07

UV .: A _mav = 258 nm (ε = 11182)

Example 9

Production of 2- / TE) - (p-chloro-phenylmethyleA) / ^r - -l- / XE) - (2'-dimethylamino-ethoxyimino27-cyclohexane

The procedure is as in Example 1, with the difference that the starting material 23.57 S (0.1 mol) 2- / 1 E) - (p-chloro-phenylmethylene ^ -cyclohexan-1-one- (E) Oxime and 12.24 g (0.105 mol) 1-dimethylamino-2-chloroethane are used, 28.60 g of the compound mentioned in the title are obtained, yield 93 »2 #.

The 2- (E) -butenedioate (l / l) melts at 168.5-171 C ⁰ . Analysis: Calculated for the formula C ₂₁ H _{27 ClN 2} O ₅ (4-22.92): C 59.64 % H 6.4-4 % Cl 8.38 K> N 6.62 % found: C 59.4-2 % H 6.38 % Cl 8.27 % N 6.67 # UV .: a _max = 275 nm (£ = 19292)

Example 10

Preparation of 2-benzyl-1- / E) - (2 ^> -dimethylamino-ethoxyimino27-cycloheptane

The procedure is as in Example 2, with the difference that 21.63 g (0.1 mol) of 2-benzyl-cycloheptan-l-one- (E) -oxime and 16.84 g (0.11 Mol) 2-dimethylamino-1-chloro-ethane hydrochloride is used. 26.96 g of the compound mentioned in the title are obtained. Yield 93.5 #. The 2- (E) -butenedioate (l / l) melts at 121 C ⁰ .

on the formula .32 % H 22nd U "f * 2 ° 5 (404 3404424 Analysis: C. 65 .47 % H 7th , 97 * N 6 .51) expected: C. 65 7th , 82 N 6 , 93 % found: example 11th , 95 *.

Preparation of 2- / iCE) -Phenylmethylen7-l-Z '(E) - (4'-methyl-piperazinyl-propoxyimino27- ^c ycloheptans

The procedure is as in Example 1, with the difference that 21.5 g (0.1 mol) of 2- (E) - -Phenylmethylene-cycloheptan-l-one- (E) -oxime and 18.55 S (0.105 mol) N-methyl-N '- (3-chloropropyl) -piperazine and benzene was used as the reaction medium instead of toluene. There are 34.67 g of the compound mentioned in the title obtained, yield 93.8 #.

The 2- (E) -butenedioate (1/2) melts at 204-208 C ⁰ . Analysis: calculated on the formula C ₅₁ H ^ ₅ N ₅ Og (601.71): C 61.88 % H 6.98 % N 7.20 % found: C 61.62 % H 6.87 $ N 7, $ 17

UV .: ^ _max = 272 nm ( I = 1370) 20

Example 12

Production of 2-ZCE) -Phenylmethylene7-l- / TE) - - (2 ⁾ -dimethylamino-ethoxyiminol7-cycloheptane

The procedure is as in Example 2, with the difference that 21.53 S (0.1 mol) of 2- (E) -phenylmethylene-cycloheptan-l-one- (E) - -oxime and 18.7 g (0.105 mol) of l-diethylainino-2-chloro-ethane hydrochloride and toluene instead of xylene as the reaction medium. 27.51 S of the compound mentioned in the title are obtained, yield 87.5 # · The 2- (E) -butenedioate (l / l) melts at 86-88 C ⁰ .

Analysis: calculated on the formula ^C 24 ^H 3 ^ ^N 2 ° 5 WO, 53): C 66.95 % H 7.96 % N 6.51 # found: C 67.12 # H 8.04 % N 6, 58 # UV .: % _mQV = 264 nm (6 = 16395)

Example 13

Production of 2 - / (E) -phenylmethylene7-l- / TE) - - (2'-diisopropylamino-ethoxyimino} _> 7-cyclohexane

The procedure is as in Example 1, with the difference that the starting material is 20.13 g (0.1 mol) 2 - / ^ E) -Phenylmethyleu7-cyclohexan-1-one- (E) - -oxime and 18.00 g (0.11 mol) of l-diisopropylamino-2-chloroethane used. 31.71 S of the compound mentioned in the title are obtained, yield 96.3 # · The 2- (E) -butenedioate (l / l) melts at 103-105 C ⁰ .

Analysis: to the formula C ₀₁ -HJ ^ N ₀ Oc (444.58)

O 36 2 5

calculated: C 67.54 % H 8.16 # N 6.30 % found: C 67.23 % H 8.32 # N 6.28 %

UV .: fl _max * 275 nm (E = 17304)

Example 14

Production of 2 - / ^ E) -Phenylmethylene7-l-ZTE) -

- (3'-dimethylamino-propoxyimino27-cyclooctane

The procedure is as in Example 1, with the difference that the starting material is 22.93 S (0.1 mol) 2- (E) -Phenylmethylene-cyclooctane-l-one-iE) -oxime and 15.11 g (0.11 mol) of 1-dimethylamino-3-chloro-propane and benzene was used as the medium instead of toluene. It will

28.40 g of the compound mentioned in the title were obtained. Yield 94.5 #.
The 2- (E) -butenedioate (l / l) melts at 136-139-C ⁰ .

-xl ■

Analysis: calculated on the formula C ₃₅ H ₅₂ N ₂ O ₅ (416.52): G 66.32 % H 7.75 # N 6.73 % found: C 65.89 ^ H 7.64 % N 6, 79 % UV .: a _max = 276 nm (£ = 14395)

Example 15

Production of the 2- / lE) -Phenylmethyleu7-l-ZTE) -

- ^ '- dimethylamino ^' - methyl-ethoxyimincO? - -cyclohexane

The procedure is as in Example 1, with the difference that 20.13 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexan-l-one- (E) -oxime and 16.6 g ( 0.105 mol) of 2-dimethylamino-2-methyl-1-chloroethane is used. 26.9 S of the compound mentioned in the title are obtained. Yield 93.9 # · The 2- (E) -butenedioate (l / l) melts at 113-117 C ⁰ . Analysis: calculated on the formula C ₂₂ H ₅₀ 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 .: a _max = 273 nm (£ = 13475)

Example 16

Production of the 2-ZTE) -Phenylmethylene7-l- / TE) -

- (2'-dimethylafiTrfo ^ ^-l.th;) xyimino27-cycloheptane

The procedure is as in Example 1, with the difference that the starting material is 21.53 g (0.1 mol) 2- (E) -Phenylmethylene-cycloheptan-l-one- (E) - -oxime and 16.6 g (0.105 mol) 2-dimethylamino-2-methyl- -1-chloroethane is used. It will be 28.61 g in the title obtained compound, yield 95.2 #.

The 2- (E) -butenedioate (l / l) melts at 120-123 C ⁰ .

Analysis: on IX the formula H C. - 23 ^H 32 ^N 2 ° 5 N 6.73 expected: C. example 66 , 32 # H 7th .75 * N 6.65 found: C. 66 .18 % a η , 62 % ^m ' ·· * au 262 nm 17595) . 17th

Production of 2- / TE) -phenylmethylene7-l-ZZE) - - (2 ⁾ -diisopropylamino-ethoxyiminol7-cyclooctane

The procedure is as in Example 1, with the difference that 22.93 g (0.1 mol) of 2- (E) -phenylmethylene-cyclooctan-l-one- (E) -oxime and 22.02 g ( 0.11 mol) l-diisopropylamino-2-chloroethane is used. There are 33.22 g of the title compound are obtained, yield 93.3 # · Melting point of the hydrochloride is 158-161 C ^0th Analysis: Calculated for the formula C ₂₅ H _{57 ClN 20} (393.0): C 70.29 % H 9, ^ 7 # Cl 9.02 % N 7.13 $ found: C 69.78 % H 9.32 % Cl 9.11 % N 7.32 % ^uv * _mav = 276 nm (£ = IWO)
^Max

Example 18

Production of the 2 - / ^ E) - (p-chloro-phenylmethylene) 7- -l - ^ "tE) - (^ '- methyl-piperazinyl-propoxyimino27- -cyclohexane

Proceed as in Example 1, with the

The difference is that 23.57 g (0.1 mol) of 2- (E) - (p-chloro-phenyl-methylene) -eyelohexan-l-one- (E) -oxime and 18.55 g (0.105 KoI) N-methyl-N '- (3-chloro-propyl) - -piperazine and, instead of toluene, xylene is used as the reaction medium. 3 ^, 4-9 g of the compound mentioned in the title are obtained. Yield: 87.6 %.

The 2- (E) -butenedioate (l / l) melts at 196-199 C ⁰ . Analysis: calculated on the formula C2qH, qC1N ^ 0q: 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 % UV = 1 _mav = 278 nm (£ = 16507)

ill 3x

Example 19

Preparation of 2 -, / CE) - (m-chloro-phenylmethylene17- -I- / J. E) - (^ '-benzyl-piperazinyl-propoxyimino} 7- -cycloheptane

Proceed as in Example 2, with the

Difference that the starting material 24-, 97 S (0.1 mol) 2 - / (E) - (m-chlorophenylmethylene) 7-cycloheptan-l-one- (E) - -oxime and 35.72 g (0.11 mol) N-Benzyl-N '- (3-chloropropyl) - -piperazine dihydrochloride used. 39.02 g of the compound mentioned in the title are obtained, yield 86 ', 5 %.

The 2- (E) -butenedioate (1/2) melts at 196-198 ° C. • Analysis: calculated on the formula G ₅₅ K ^ ₂ ClN ₅ O ₉ (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 .: ^ _max = 274- nm (£ = 13700)

Claims (9)

Claims R is an optionally substituted by 1-3 halogen atom (s) and / or lower alkoxy group (s) Denotes phenyl group; 2
R and R each stand for hydrogen or together one Form valence bond; A represents lower alkylene; -5 4
R and R each represent hydrogen or lower alkyl stand or together with the nitrogen atom, to which they are bound form a 5-8- membered heterocyclic ring, which optionally contain a further oxygen or nitrogen atom and / or phenyl-lower alkyl may be substituted by lower alkyl, phenyl; and
η stands for 5, 4, 5, 6 or 7) and pharmaceutically acceptable acid addition salts thereof by reacting an oxime of the general formula II (CH ₂ ) _n C = N - OH (II) with a halogen compound of the general formula III 10 Hal A N _R 3 (in which Hal stands for halogen and R, R ¹ , R ² , R ⁵ , R ^, A and η have the above meanings), characterized in that the reaction of the oxime of the general formula II and the halogen compound of the general formula III or an acid addition salts thereof in the presence a lower alkali metal alcoholate and an aromatic organic hydrocarbon and, if desired, the compound of the general formula I obtained in this way by known methods Acid addition salt transferred. 2. The method according to claim 1, characterized in that the alkali metal alcoholate Sodium methylate, sodium ethylate, potassium methylate, Potassium ethylate or potassium tert. butylate used. 3. The method according to claim 1 or 2, characterized in that as aromatic organic hydrocarbon benzene, toluene or xylene or a mixture thereof is used. 4. The method according to any one of claims 1-3> characterized in that the reaction with heating, advantageous when Performs boiling point of the reaction mixture. 5. Method according to one of claims 1-4, characterized in that the reaction is carried out within 1-2 hours. 6. The method according to any one of claims 1-5 for the production of 2- / TE) -Pheriylmethylene7-l-Z.lE) - (3'- -diisopropylamino-propoxyimino ^ -cyclohexane through Conversion of 2 ~ (E) -phenylmethylene-cyclohexan-l-one- (E) - -oxime and l-diisopropylamino-3-chloropropane, characterized in that the reaction is carried out in the presence of Sodium methylate and toluene. 7. The method according to claim 1 for the preparation of 2-ZTE) - (p-chlorophenylmethylenel7-l-ZX ^E ) - (3 ^I -diisopropylamino-propoxyiminol7-cyclohexane by reacting 2- _> / XE) - (p-chloro-phenylmethylene2 / -cyclohexanr-l-one- - (E) -oxime and l-diisopropylamino-3-chloro-propane, characterized in that the reaction is carried out in the presence of Sodium methylate and toluene. 8. The method according to claim 1 for the preparation of 2-benzal-1- (2'-diisopropylamino ~ ethoxyimino) cycloheptane by reacting 2-benzal-cycloheptanone-oxime and 2-diisopropylamino-ethyl chloride, characterized in that one carries out the reaction in the presence of Sodium methylate and toluene. 3A04424 -S- 9. The method according to any one of claims 1-8, characterized in that that the alkanol formed in the reaction together with the aromatic organic hydrocarbon distilled off.