FR2540494A1 - PROCESS FOR THE PREPARATION OF BASIC OXIME ETHERS - Google Patents

Abstract

THE PRESENT INVENTION RELATES TO A PROCESS FOR THE PREPARATION OF BASIC OXIME ETHERS. THE PRODUCTS CONFORMING TO THE INVENTION, WHICH CORRESPOND TO GENERAL FORMULA I BELOW: (CF DESIGN IN BOPI) ARE PREPARED BY REACTION OF AN OXIME OF GENERAL FORMULA II: (CF DESIGN IN BOPI) ON A HALOGEN COMPOUND OF GENERAL FORMULA III: (CF DRAWING IN BOPI)

Description

The present invention relates to a new

  improved compound for the preparation of basic oxime ethers.

  In accordance with the present invention, there is provided a process for preparing compounds represented by the following general formula (I) H = N A-Ni / I

-1

R-C-R 1

  H and acid addition salts thereof, (wherein: R is a phenyl group optionally substituted with one to three halogen atoms and / or lower alkoxy groups; R 1 and R 2 are each an atom of hydrogen or together form a valence bond, A is a lower alkylene radical;

3 4

  R 3 e R are each a hydrogen atom or a lower alkyl group or they form with the adjacent nitrogen atom

  to which they are attached, a heterocyclic ring of 5-8 members

  which may possibly contain another atom of oxygen.

  annoyance or nitrogen and / or may be optionally substituted by

  a lower alkyl phenyl or phenyl-lower alkyl radical

laughter, and

n is 3, 4, 5, 6 or 7).

  The compounds represented by the general formula (I) are known and they exhibit anti-depressant effects;

  antiparkinsonian and local anesthetic (Hungarian Patent No. 169298).

  According to this description, the compounds of formula 9

  narale (1) can be prepared, inter alia, by the conden-

  of a compound represented by the general formula (II)

after

(CH C = N-OH)

-R

R-C-R H

  with a compound represented by the general formula (III)

after

3

  Hal-AN (III) 4 in an inert solvent, in the presence of a basic condensing agent (in the formulas, R, R, R, R, R and N are as defined above) In the examples of the present patent -above,

  organic solvents exclusively (toluene, ethanol, ben-

  zene or xylene) are used as the inert solvent, while

  sodium hydride, sodium amide and sodium

  that are applied as the basic condensation agent.

  According to this description, without any experimental support

  alkali metal hydroxides can also be used as the basic condensation agent and in this case

the water serves as a solvent.

  The procedure described in the above patent faces serious difficulties, in particular in the context of a production on an industrial scale the haloalkylamines of general formula (III) can be used only in the form of bases free, which are very unstable compounds, highly susceptible to dimerization and polymerization reactions;

  the specific capacitance factor of the switchgear is de-

  favorable; the reaction time is long (12 to 16 hours);

  organic solvents used as a reaction medium

  feel the risk of ignition and explosion; the reaction temperature is relatively high (130 ° C), the final product is isolated by complicated methods (decomposition of sodium hydride or sodium amide, acid or alkaline extractions, trans -precipitations, etc.);

  purification is accomplished by vacuum distillation under vacuum.

  se, which requires complicated and special equipment; the hydrogen gas formed in the reaction constitutes a risk of explosion and the ammonia that emerges, a pollution of the environment,

  in some cases, isomerization takes place in the reaction.

  The last disadvantage is shown by the fact that

  when 2-Z (E) - (p-chloro-phenylmethylene) 7-1-Z (E) - (3 '-

  diisopropylamino-propoxyimino) 7-cyclohexane is prepared according to

  the description of the Hungarian patent N O 169 298, it is formed in

  plus the desired product, a substance of unknown structure, in a significant amount, whose physicochemical parameters differ considerably from those of the desired product The UV spectrum of the two products indicates, while the value of 'of the max

  desired compound is 280 nm (e = 17456.15), that the correct value

  of the unknown substance is A max 243 nm

(= 1245).

  This difference shows that during the reaction,

  an unwanted secondary reaction (isomerization) takes place.

  Hungarian Patent No. 0-169,298 describes the preparation

  new active compounds from the pharmaceutical point of view

  the object of the invention was to provide new compounds in an amount sufficient to allow the identification of the

  product and pharmacological tests On the other hand, the ob-

  of the present invention is to provide a method for the

  preparation of the known compounds of general formula (1), which

  is easy to achieve at the scale of an industrial production-

  the, also, removes the above disadvantages of

  known and meets the requirements of the protection of the

  environment, energy savings and the industrial economy.

  In accordance with the present invention, there is provided a

  process for the preparation of basic oxime ethers,

  with the general formula (I) (wherein: R is a phenyl group optionally substituted with one to three halogen atoms and / or lower alkoxy groups;

  R 1 and R are each a hydrogen atom or they together form

  a valence bond; A is a lower alkylene radical R 3 and R are each a hydrogen atom or an alkyl group

  lower, or they form with the adjacent nitrogen atom

  which they are fixed, a heterocyclic ring of 5 to 8 mem-

  which may possibly contain another atom of oxygen.

  gene or nitrogen and / or may be optionally substituted by

  a lower alkyl phenyl or phenyl-lower alkyl radical

laughter, and is 3, 4, 5, 6 or 7),

  and their acid addition salts,

  by the reaction of an oxime of general formula (II) with a halogenated compound of general formula (III) (where Hal represents a halogen atom and R, R 1, R 2, R 3 R 4, A and N are as defined above), according to which the reaction of the compound of general formula (II) with the halogenated compound is carried out

  of general formula (III), or an acid addition salt thereof

  ci, in a mixture of water and a water-miscible organic solvent, in the presence of an alkali metal hydroxide and a phase transfer catalyst represented by the following general formula (IV):

R 7 (IV)

  wherein R 5 and R 6 are each a lower alkyl group, or they form with the adjacent nitrogen atom to which they are

  fixed, a 5- to 8-membered heterocyclic ring, which may

  to contain another oxygen or nitrogen atom and / or

  may be substituted by a lower alkyl group

  phenyl or phenyl-lower alkyl and R 7 is a group represented by the following general formula (a): Hal-A (a) or (b)

(C 2 vn C = N-O-A-

% "C A-R 2 lb /

R-C-R

  Wherein Hal, A, n, R, R 1 and R are as defined above) and, if desired, converting a compound of general formula (I) thus obtained into an acid addition salt.

  of it, by known methods.

  It has been found that in the case where the reaction of the com-

  of general formula (II) with the halogenated compound of

  a general mule (III) or a salt thereof, is carried out in

  the presence of an alkali metal hydroxide in an aqueous medium,

  the desired compound of general formula (I) is obtained only

  Average yields The present invention is based on the

  according to which, in the case where an oxime of formula

  (II) is treated with a haloalkylamine of

  (III) 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 catalyst

  phase transfer of general formula (IV), the disadvantages

  above-mentioned methods of the known method can be removed and the desired compound of general formula (I) is obtained in the form of

  extremely pure and with excellent yields.

  The term "lower alkoxy group" here includes

  straight-chain or branched alkoxy groups having 1 to 4 carbon atoms

  carbon monoxide (for example, methoxy, ethoxy, n-propoxy, iso-

  propoxy, etc.) The term "halogen atom" includes fluorine, chlorine, bromine and iodine. The term "lower alkylene" refers to straight or branched chain alkylene groups having 2 to 4 carbon atoms ( for example ethylene, trimethylene or 1-methyl-ethylene). 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.).

  Groups R 3 and R 4 can form with the atom

  of adjacent nitrogen to which they are attached, a heterocyclic ring

  which may optionally contain another oxygen or nitrogen atom and / or may be optionally substituted. The heterocyclic group may be, for example, a morpholino radical,

  pyrrolidino, piperidino, N-methyl-piperazino, N-phenylpiperazine

zino or N-benzyl-piperazino etc.

  n is preferably 4 or 5.

  The acid addition salts of the compounds of formula

  (I) may be acceptable acid addition salts.

  from the pharmaceutical point of view, formed with acids

  minerals or organic substances (eg hydrochlorides, bromine

  hydrates, sulphates, maleates, fumarates, acetates, lactates, etc.). In accordance with the method of the present invention, a

  any alcohol, ether or ketone that is miscible with water;

  methylformamide, dimethylsulfoxide, pyridine, triamine

  Hexamethylphosphoric acid or sulfolane can be used as a water-miscible organic solvent. It is preferable to use dimethylsulfoxide, acetonitrile, tetrahydrofuran or dimethylformamide as

solvent miscible with water.

  As an alkali metal hydroxide, it is possible to apply

  lithium, sodium or potassium hydroxide, and preferably

  sodium hydroxide, potassium hydroxide or a

mixture of these.

  It is preferred to use the compound of general formula

  (III) in the form of an acid addition salt thereof.

  ci, especially in the form of an addition salt formed

  with a mineral acid, especially the hydrochloride.

  The reaction is carried out at 40 80 C, preferably at a temperature between 50 and 60 C. Under these conditions, the reaction takes place rapidly, the reaction time is between

  minutes and 3 hours, especially 1 to 2 hours.

  The phase transfer catalyst of general formula

  (IV) may be either a starting material of the formula R 7

  (III) (i.e., R is a group of general formula

   neral (a)), ie a final product of general formula (I)

  (i.e., R is a group of general formula (b)).

  The reaction mixture can be treated according to methods known per se. It is possible to proceed by extracting the final product with a non-miscible organic solvent.

  water, which does not react with alkali (for example a hydro-

  aromatic carbide, such as benzene, toluene or xylene),

  washing the extract to neutrality and evaporating -

  The compounds of general formula (I) thus obtained can be converted into their acid addition salts according to

  in a known manner, by the reaction with a corresponding acid,

  in an inert organic solvent.

  In accordance with a preferred aspect of the method of

  the present invention, 2 - / (E) - (p-chloro-phenyl)

  methylene) 7-1 (E) - (3'-diisopropylamino-propoxyimino) 7-cyclohexyl

  hexane by reacting 2 (E) - (p-chloro-phenylmethylene) 7

  cyclohexane-1-one- (E) -oxime with 1-diisopropyl hydrochloride

  propylamino-3-chloropropane in a mixture of water and di-

  methylformamide, in the presence of sodium hydroxide and hy-

potassium hydroxide.

  The advantages offered by the process according to the

  The present invention is as follows: the process is easy

  feasible for production on an industrial scale, also (short reaction time, relatively

  low; simple insulation; no purification by distillation

  under high vacuum, requiring complicated equipment

  and special is not required; Dolez's reactions

  explosion risks and environmental pollution problems are eliminated; explosive and flammable organic media are replaced by a safe aqueous medium), secondary reactions are repressed and a product

  High purity is obtained, with excellent yields.

Example 1

  Preparation of 2 (E) -phenylmethylene / -1 (E) - (4 '-

  phenyl-piperazinyl-propoxyimine) 7-cyclohexane In an apparatus equipped with a stirrer, ml of water, 40 g of sodium hydroxide and 10 g of potassium hydroxide are placed. After complete dissolution, a solution of 20.1 g. g

  (0.1 mole) 2- (E) -phenylmethylene-cyclohexane-1-one- (E) -

  oxime and 30 ml of dimethyl sulfoxide is introduced and then

  32.73 g (0.105 mol) of N-phenyl-N '- (3) dihydrochloride

  chloro-propyl) -piperazine are added in several portions.

  The reaction mixture is maintained at 50 ° C for 1 to

  2 hours The reaction mixture is subjected to a post-reaction

  for a few hours at room temperature,

  in 150 g of ice water and extracted with benzene.

  The benzene solution is washed to neutrality and evaporated.

  Thus, 33.09 g of the desired product is obtained, yield 82%.

  The hydrochloride melts at 189.5 193.50 C. Analysis: for Formula C 26 H 34 C 1 N 30 (440.04) Calculated values: C 70.97% H 7.79% Cl 8.06% N 9 , 55% Found values: C 70.97% H 7.98% C 1 7.94% N 9.46%

Example 2

  Preparation of 2-L (E) -phenylmethylene) 7-1-Z (E) -

  (4'-methylpiperazinylpropoxyimino) 7-cycloheptane.

  In an apparatus equipped with a stirrer, ml of water, 20 g of sodium hydroxide and 10 g of hydroxide are introduced.

  Once completely dissolved, a solution is added

  21.5 g (0.1 mole) of 2- (E) -phenylmethylene-cyclohexyl

  heptane-1-one- (E) -oxime and 20 ml of dimethylsulfoxide, the mixture is maintained at 60 ° C. for half an hour, then

  add 18.55 g (0.105 mol) of N-methyl-N '- (3-chloropropyl) -

  piperazine The reaction mixture is stirred at 60 ° C. for 2 hours, poured at room temperature into a mixture of

  g ice water and 100 ml benzene; the benzene layer

  separated, washed to neutrality with water and evaporated

  Thus, 33.38 g of the desired compound are obtained.

  yield 90.3% 2E) -butenedioate (1/2) melts at 204 -

208 C.

  Analysis: for Formula C 31 H 43 N 309 (601.71) Calculated values: C 61.88% H 6.98% N 7.20% Found values: C 62.03% H 7.20% N 7, 12%

UV: Max = 272 nm (E = 1370).

max

Example 3

  Preparation of 2-Z (E) (m-chloro-phenylmethylene) 7-

  1-Z (E) - (4'-benzyl-piperazinyl-propoxyimino) 7-cycloheptane.

  In an apparatus equipped with an agitator, one introduces

  ml of water and 50 g of potassium hydroxide After dissolu-

  complete solution, a solution of 24.97 g (0.1 mol) is added

  2-t (E) (r-chloro-phenylmethylene) / - cycloheptan-1-one- (E) -

  oxime in 25 ml of acetonitrile The mixture is left

  at 60 ° C. for one hour, then 35.72 g (0.11 mol) of

  N-benzyl-N "- (3-chloropropyl) -piperazine hydrochloride are

  When the addition is complete, the reaction mixture is subjected to a post-reaction at 60 ° C. for 2 hours, poured into 100 g of crushed ice, extracted

  with dichloroethane and the organic phase is evaporated.

  Thus, 36 g of the desired product are collected, yield 79.8%

  2- (Z) -butenedioate (1/2) melts 196 199 C.

  Analysis: For Formula C 35 H 42 C 1 N 309 (684.20) Calculated: C 61.44% H 6.18% Cl 5.18% N 6.14% Found: C 61.58% H 6.34% C 1 5.21% N 6.24%

UV: max 274 nm (g = 13700).

max

Example 4

  Preparation of 2- (E) -phenylmethylene-1-Z (E) - (4 '-

  benzyl-piperazinyl-ethoxyimino) 7-cycloheptane. In an apparatus equipped with a stirrer, 50 ml of water and 50 g of sodium hydroxide are introduced. After complete dissolution, a solution of 21.53 g (0.1 mole) of 2- (E) - is added. phenylmethylene-cycloheptan-1-one- (E) -oxime in 25 ml

  tetrahydrofuran, for 34.19 g (0.11 mol) of dichlorhydrin,

  N-benzyl-N '- (2-chloroethyl) piperazine nitrate and the reaction mixture is added at 50 ° C. for 2 hours, poured into 200 g of ice water, extracted with a portion of 100 ml and two 50 ml portions of benzene and the

  combined extracts Thus, 40.4 g of the desired compound are obtained.

  The yield is 97%. The dihydrochloride melts at 206 ° C.

  Analysis: for Formula C 27 H 36 Cl N 30 (489.62) Calculated values: C 66.23% H 7.43% C 1 14.56% N 8.58% Found values: C 65.95% H 7.49% CI 14.27% N 8.42% UV: x = 262 nm (ú = 17012) max

Example 5

  Preparation of 2- (E) (p-chloro-phenylmethylene) /

  -1-L (E) - (4'-methylpiperazinylpropoxyimino) - cyclohexane.

  In an apparatus equipped with an agitator, one introduces

  ml of water, 40 g of potassium hydroxide and 10 g of hydro-

  after complete dissolution, add a

  solution of 23.57 g (0.1 mole) of 2 (E) - (p-chlorophenyl)

  thylene) 7-cyclohexane-1-one- (E) -oxime in 20 ml of dimethyl

  formamide, followed by 18.55 g (0.105 mole) of N-methyl-N '- (3-chloro)

  propyl) -piperazine The reaction mixture is stirred at 70 ° C. for 2 hours, poured into 150 g of ice water and extracted with chloroform. The extract is dried over anhydrous magnesium sulphate and evaporated. g of the desired compound, Y yield 92.7% 2- (E) butenedioate

(1/2) melts at 196,199 C.

  Analysis: for Formula C 29 H 38 C 1 N 309 (608.1) Calculated values: C 57.28% H 6.29% C 1 5.83% N 6.91%

5409 4

  Found values: C 57.35% H 6.21% Cl 5.97% N 6.81%

UV: max = 278 nm (c = 16507).

  EXAMPLE 6 Preparation of 2-Z (E) - (o-chloro-phenylmethylene) 7-1-Z (E) - (4'-benzyl-piperazinyl-propoxyimino) - cyclohexane. The procedure of Example 4 is repeated, except

  23.57 g (0.1 mole) of 2 - / - (E) - (o-chlorophenyl)

  nylmethylene) / - cyclohexan-1-one (E) -oxime and 35.72 g (0.11 g)

  mole) of N-benzyl-N '- (3-chloropropyl) -piperidine dihydrochloride

  Razine as starting materials Thus, 39.02 g of the desired compound are collected, yield: 86.3% 2- (E) -butenedioate

(1/2) melts at 196 201 C.

  Analysis: For Formula C 35 H 42 C 1 N 304 (684.2) Calculated: C 61.44% H 6.15% C 5.19% N 6.14% Found: C 61.37% H 6.35% C 1 5.3% N 5.97% UV: kmax = 269 nm (c = 11573)

Example 7

  Preparation of 2 (E) - (2 ', 4'-dichloro-phenylmethyl)

  lene) / - l (E) (4'-benzyl-piperazinyl-propoxyimino) / cyclopentyl

hexane.

  The procedure of Example 1 is repeated, except

  that 27.02 g (0.1 mole) of 2 (E) - (2 ', 4'-dichloride) are used.

  ro-phenylmethylene) / - cyclohexane-1-one- (E) -oxime and 35.72-g

  (0.11 mole) N-benzyl-N '- (3-chloropropyl) dihydrochloride

  piperazine as starting materials 39.56 g of the desired compound are thus obtained, yield: 81.3% 2- (E) -butenedioate

(1/2) melts at 198.5 201.5 C.

* Analysis: for Formula C 35 H 41 C 12 N 309 (718.65) Calculated values: C 58.5% H 5.75% Cl 9.86% N 5.84% Found values: C 58.7% H 5.75% Cl 9.72% N 5.83%

UV: at max = 273 nm (c = 15409).

Example 8

  Preparation of 2-Z (E) - (m-chloro-phenylmethylene) 7-

  1-Z (E) - (4'-benzyl-piperazinyl-ethoxyimino) 7-cyclohexane.

  The procedure of Example 3 is repeated, except

  23.57 g (0.1 mole) of 2-L (E) - (m-chlorophenyl)

  nylmethylene) 7-cyclohexane-1-one- (E) -oxime and 34.2 g (0.11 g)

  mole) of N-benzyl-N '- (2-chloroethyl) -piperidine dihydrochloride

  razine as starting materials Thus, 40.62 g of the desired product are obtained, yield: 92.7% 2- (E) -butenedioate (1/2)

background at 196; 5,199.5 C.

  Analysis: for Formula C 34 H 40 Cl N 304 (670.18) Calculated values: C 60.94% H 6.02% C 1 5.3% N 6.27% Found values: C 60.1% H 6.01% C 1 5.37% N 6.12%

UV: λ max = 274 nm (E = 15246).

Example 9

  Preparation of 2- (E) -phenylmethylene-1-L (E) - <{2 '-

  dimethylamino-2'-methylethoxyimino) 7-cycloheptane.

  The procedure of Example 2 is repeated, except

  21.53 g (0.1 mole) of 2- (E) -phenylmethylene-

  cycloheptan-1-one- (E) -oxime and 16.6 g (0-105 moles) of 2-di-

  Inmethylamino-2-methyl-1-chloroethane as starting materials.

  Thus, 28.46 g of the desired compound are obtained, yield: 94.7%

  2- (E) -butenedioate (1/1) melts at 120 ° C.

  Analysis: for Formula C 23 H 32 N 205 (416.51) Calculated values: C 66.32% H 7.75% N 6.73% Found values: C 66.48% H 7.95% N 6, 70%

UV: k = 262 nm (E = 17595).

max

Example 10

  Preparation of 2- (E) -phenylmethylene-1 (E) - (2 '-

  dimethylamino-2'-methylethoxyimino) 7-cyclohexane.

  The procedure of Example 3 is repeated, except

  that 20.13 g (0.1 mole) of 2- (E) -phenylmethylene-

  cyclohexane-1-one- (E) -oxir e and 16.6 g (0.105 mole) of 2-dimethyl-

  thylamino-2-methyl-1-chloroethane as starting materials.

  26.9 g of the desired compound are thus collected, yield:

  93.9% 2- (E) -butenedioate (1/1) melts at 113-117 ° C.

  Analysis: for Formula C 22 H 30 N 205 (402.48) Calculated values: C 65.64% H 7.51% N 6.96% Found values: C 65.98% H 7.60% N 7, 00%

UV: = 273 nm (E: 13475).

max

L 3404 9 4

Example 11

  Preparation of 2- (E) -phenylmethylene-1-Z (E) (2 '-

  diisopropylamino-ethoxyimino) / - cyclooctane. The procedure of Example 4 is repeated except that 22.93 g (0.1 mole) of 2- (E) phenylmethylene is used.

  cyclooctane-1-one- (E) -oxime and 22.02 g (0.11 mol) of 1-di-

  isopropylamino-2-chloroethane as starting materials

  thus obtaining 31.62 g of the desired product, yield: 88.7%.

The hydrochloride melts at 158 161 C.

  Analysis: for Formula C 23 H 37 C 1 N 20 (393.0) Calculated values: C 70.29% H 9.47% C 1 9.02% N 7.13% Found values: C 70.44% H 9.5% Cl 8.98% N 7.23%

UV: max 276 nm (E = 14170).

max Exe on the 12th

  Preparation of 2- (E) -phenylmethylene-1-L (E) - (3 '-

  dimethylamino-propoxyimino) 7-cyclooctane. The procedure of Example 1 is repeated, except

  that 22.93 g (0.1 mol) of 2- (E) -phenylmethylene-

  cyclooctane-1-one- (E) -oxime and 17.39 g (0.1 mole) of

  1-dimethylamino-3-chloropropane drate as

  Thus, 27.35 g of the desired compound,

  91% 2- (E) -butenedioate (1/1) melts at 136 138.5 C Analysis: for Formula C 23 H 32 N 205 (416.52) Calculated values C 66232% H 7, 75% N 6.73% Findings C 66.74% H 7.96% N 6.61%

U Vo: 1 max = 276 nm (c = 14395).

Exele 13

  Preparation of 2- (E) -phenylmethylene-1-Z (E) - (2 '-

  dimethylamino-ethoxyimino) 7-cycloheptane. The procedure of Example 3 is repeated, except

  21.53 g (0.1 mole) of 2- (E) -phenylmethylene-

  cycloheptane-1-one- (E) -oxime and 18.07 g (0.105 mol) of

  dimethylamino-2-chloroethane hydrate as

  Thus, 28.99 g of the desired compound are obtained.

  92.2% 2- (E) -butenedioate (1/1) melts at 86 88 Co Analysis: for Formula C 24 H 34 N 205 (430.53) Calculated: C 66.95% H 7 , 96% N 6.51% Found values: C 67.12% H 8.06% N 6.46%

UV: max = 264 nm (E = 16395).

Example 14

  Preparation of 2- (E) -phenylmethylene-1-Z (E) - (2 '-

  diisopropylamino-ethoxyimino) 7-cyclohexane. The procedure of Example 1 is repeated, except

  that 20.13 g (0.1 mole) of 2- (E) -phenylmethylene-

  cyclohexane-1-one- (E) -oxime and 22.02 g (0.11 mol) of

  1-diisopropylamino-2-chloroethane hydrate as materials

  Thus, 30.99 g of the desired compound are obtained.

  94.3% 2- (E) -butyldieneoate melts at 103 ° C.

  Analysis for Formula C 25 H 36 N 205 (444.58) Calculated: C 67, 54% H 8.16% N 6.30% Found: C 67.54% H 8.34% N 6834%

UV: max = 275 nm (υ = 17304).

max

Example 15

  Preparation of 2-benzyl-1-L (E) - (2'-dimethylamino)

ethoxyimino) 7-cycloheptane.

  The procedure of Example 1 is repeated, except

  21.63 g (0.1 mol) of 2-benzylcycloheptane are used.

  1-one (E) -oxime and 16.84 g (0.11 mole) of 2-chlorohydrate

  dimethylamino-1-chloroethane as starting materials. Thus, 26.17 g of the desired compound are obtained. Yield: 90.7%.

  2- (E) -butenedioate (1/1) melts at 121 124 C.

  Analysis: for Formula C 22 H 32 N 205 (404.51) Calculated values: C 65.32% H 7.97% N 6.93% Found values: C 65.77% H 8.04% N 7, 11%

Example 16

  Preparation of 2-Z (E) - (p-chloro-phenylmethylene) 7-

  1-Z (E) - (2'-dimethylamino-ethoxyimino) 7-cyclohexane.

  The procedure of Example 2 is repeated, except

  23.57 g (0.1 mol) of 2- (E) - (p-chlorophenyl)

  methylene) 7-cyclohexane-1-one- (E) -oxime and 12.24 g (0.105 mol)

  1-dimethylamino-2-chloroethane as starting materials.

  Thus, 28.97 g of the desired compound are obtained, yield:

  94.4% 2- (E) -butenedioate (1/1) melts at 168.5 to 170.5 C.

  Analysis: for Formula C 21 H 27 Cl N 205 (422.92) Calculated values: C 59.64% H 6.44% C 1 8.38% N 6.62% Found values: C 59.97% H 6.74% C 1 8.28% N 6.46% UV: At max = 275 nm (c = 19292)

Example 17

  Preparation of 2-Z (E) - (p-chloro-phenylmethylene) / 7-1-Z (E) - (3'-diisopropylamino-propoxyimino) cyclohexane The procedure of Example 1 is repeated, except

  23.57 g (0.1 mole) of 2 l (E) - (p-chlorophenyl)

  nylmethylene) 7-cyclohexane-1-one- (E) -oxime and 23.55 g (0.11 g)

  mole) of 1-diisopropylamino-3-chloropropyl dihydrochloride

  as starting materials Thus, we obtain 35.63 g of the com-

  desired dosage, yield: 94.5% 2- (E) -butenedioate (1/1)

bottom 87 87.5 C.

  Analysis: for Formula C 26 H 37 C 1 N 205 (493.06) Calculated values: C 63.34% H 7.56% Cl 7.19% N 5.68% Found values: C 63.30% H 7.54% Cl 7.13% N 5.60% UV 1 max = 280 nm (E = 17456.15).

max

Example 18

  Preparation of 2 (E) -phenylmethylene-1 (E) (3 '-

  diisopropylamino-propoxyimino) 7-cyclohexane.

  The procedure of Example 1 is repeated, except

  that 20.13 g (0.1 mole) of 2- (E) -phenylmethylene-

  cyclohexane-1-one- (E) -oxime and 23.55 g (0.11 mol) of

  1-diisopropylamino-3-chloropropane drate as

  Thus, 31.99 g of the desired compound are obtained.

  93.4% o 2- (E) -butenedioate (1/1) melts at 128.5 -

, 50 C.

  Analysis: for Formula C 26 H 3 8 N 205 (458.61) Calculated values: C 68.09% H 8.35% N 6.10% Found values: C 68.28% H 8.35% N 6 , 28% UV: kmax = 275 nm

254049-4

Example 19

  Preparation of 2- (Z) -phenylmethylene-1-L (E) - (2 '-

  diisopropylamino-ethoxyimino) 7-cycloheptane. The procedure of Example 1 is repeated except that 21.53 g (0.1 mole) of 2- (Z) phenylmethylene is used.

  cycloheptan-1-one- (E) -oxime and 22.02 g (0.11 mole) of dichloride.

  1-diisopropylamino-2-chloroethane hydrate as materials

  Thus, 32.58 g of the desired compound are obtained.

  95.1% 2- (E) -butenedioate (1/1) melts at 117 120 C.

  Analysis: for Formula C 26 H 38 N 205 (458.6) -

  Calculated values: C 68.09% H 8.35% N 6.11% Found values: C 68.33% H 8.46% N 6.13% UV: At max = 258 nm (s = 11182)

Example 20

  Preparation of 2- (E) -phenylmethylene-1-L (E) - (2 '-

  diethylaminoethoxyimino) cyclopentane The procedure of Example 2 is repeated, except

  18.7 g (0.1 mole) of 2- (E) -phenylmethylene-

  cyclopentane-1-one- (E) -oxime and 14 g (0.1 mole) of 1-dimethyl-

  Thylamino-2-chloroethane as starting materials. Thus, 29.48 g of the desired compound are obtained. Yield: 82.5%.

  2- (E) -butenedioate (1/1) melts at 123 124 C.

  Analysis: for Formula C 22 H 30 N 205 (402.50) Calculated values: C 65.65% H 7.51% N 6.96% Found values: C 65.50% H 7.42% N 6, 95% UV: max = 304 nm (υ = 25800), max

Example 21

  Preparation of 2- (E) -phenylmethylene-1 (E) (2 '-

  diethylamino-ethoxyimino) 7-cyclohexane. The procedure of Example 1 is repeated, except

  that 20.13 g (0.1 mole) of 2- (E) -phenylmethylene-

  cyclohexane-1-one- (E) -oxime and 18.93 g (0.11 mol) of

  1-diethylamino-2-chloroethane drate as starting materials

  Thus, 32.28 g of the desired compound are obtained, yield:

  77.5% 2- (E) -butenedioate (1/1) melts at 111 112 C.

54045 4

  Analysis: for Formula C 23 H 32 N 205 (416.53) Calculated values: C 66> 33% H 7.74% N 6.72% Found values: C 65.92% H 7.60% N 6, 70%

UV: max = 275 nm (E = 15300).

Example 22

  Preparation of 2- (E) -phenylmethylene-1-Z (E) - (2 '-

  dimethylaminoethoxyimino) 7-cyclopentane The procedure of Example 1 is repeated, except

  18.7 g (0.1 mole) of 2- (E) -phenylmethylene-

  cyclopentane-1-one- (E) -oxime and 16.07 g (0.105 mol) of

  1-dimethylamino-2-chloroethane hydrate as materials

  Thus, 26.96 g of the desired compound are obtained.

  77.0% 2- (E) -butenedioate (1/1) melts at 126 -

128 C.

  Analysis: for Formula C 20 H 26 N 205 (374.44) Calculated values: C 64.18% H 7.00% N 7.47% Found values: C 64.00% H 6.87% N 7, 44%

UV: λ max = 303 nm (υ = 23587).

max

Example 23

  Preparation of 2- (E) -phenylmethylene-1-L (E) - (2 -

  dimethylamino-ethoxyimino) 7-cyclohexane. The procedure of Example 2 is repeated, except

  that 20.13 g (0.1 mole) of 2- (E) -phenylmethylene-

  cyclohexane-1-one- (E) -oxime and 11.8 g (0.11 mol) of 1-dimethyl

  thylamino-2-chloroethane as starting materials Thus,

  30.02 g of the desired compound are obtained, yield: 77.3%.

  2- (E) -butenedioate (1/1) melts at 141 143 C.

  Analysis: for Formula C 21 H 28 N 205 (388.47) Calculated values: C 64 D 92% H 7.27% N 7.21% Found values: C 64> 71% H 7.11% N 7, 20%

UV: max = 275 nm (E = 15927).

Example 24

  Preparation of 2 (E) - (p-chloro-phenylmethylene) / 7-

  1-Z (E) - (3'-dimethylamino-propoxyimino) 7-cycloheptane.

  The procedure of Example 2 is repeated, except

  24.93 g (0.1 mole) of 2-Z (E) - (p-chlorophenyl) are used.

  methylene) / - cycloheptan-1-one- (E) -oxime and 13.3 g (0.11 parts) of 1-dimethylamino-3-chloropropane as

  Thus, 33.15 g of the desired compound are obtained.

  73.5% 2- (E) -butenedioate (1/1) melts at 160 161 C. Analysis: for Formula C 23 H 31 Cl N 205 (450.97) Calculated values: C 61.22% H 6.94% N 6.22% Found values: C 61.12% H 6.73% N 6.20%

UV: max = 268 nm (s = 19759).

  As can be seen from the foregoing, the invention is in no way limited to those of its modes of implementation, of realization and of application which have just been described more explicitly; it embraces on the contrary

  all the variants that may come to the mind of the

  in this respect, without departing from the scope or scope,

of the present invention.

º 5404 O 4

Claims (9)

1. A process for the preparation of oxime bicyclic ethers represented by the following general formula (I): ## STR5 ## 1.C H   (wherein R is a phenyl group optionally substituted with one to three halogen atoms and / or lower aleoxy groups;   R 1 and R 2 are each a hydrogen atom or together they form   a valence link; A is a lower alkylene radical; 3 4   R and R are each a hydrogen atom or a lower alkyl radical, or they form with the adjacent nitrogen atom   to which they are attached, a heterocyclic ring of 5-8 members   which may possibly contain another atom of oxygen.   annoyance or nitrogen and / or may be optionally substituted by   a lower alkyl, phenyl or phenyl-lower alkyl group and N is 3, 4, 5, -6 or 7),   and their acid addition salts, by the reaction of an oxi-   represented by the following general formula (II): / II / R.C-R 1   H with a halogenated compound represented by the following general formula (III): Hal-A-N (III) - 4   (in which Hal represents a halogen atom and R, R 1, R 2, R R, A and N are as defined above),   characterized in that the reaction of the compound of   general mule (II) with the halogenated compound of general formula   (III) or an acid addition salt thereof, in a   mixture of water and a water-miscible organic solvent, in pre-   the presence of an alkali metal hydroxide and a catalyst of   phase transfer represented by the general formula (IV) after: 5 R 7-N / (IV)   R 6 in which R 5 and R 6 are each a lower alkyl radical, or they form with the adjacent nitrogen atom to which they are   a 5- to 8-membered heterocyclic ring, which may   to contain another oxygen or nitrogen atom and / or   may be substituted by an alkyl radical   phenyl or phenyl-lower alkyl and R 7 is a group of general formulas (a) or (b) hereinafter Hal-A (a) CH 2 N 2 = N-O-A- C-R / B / RC_R 1 X H R 1 2   (wherein Hal, A, n, R, R and R 2 are as defined above) and if desired, converting a compound of general formula (I) thus obtained into an acid addition salt   of it, by known methods.   2. Method according to claim 1, characterized in that a water-miscible alcohol, ether or ketone or acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine, hexamethylphosphoric acid triamide or hexamethylphosphoric acid is used.   sulfolane as an organic solvent miscible with water.   3. Process according to claim 2, characterized in that dimethylsulfoxide, acetonitrile, tetrahydrofuran or dimethylformamide are used as solvents. organic miscible with water.   4. Method according to one of claims 1 to 3,   characterized in that sodium hydroxide, potassium hydroxide or a mixture thereof is used as a alkali metal hydroxide.   5. Method according to one of claims 1 to 4,   characterized in that the halogenated compound of formula   general (III) in the form of an addition salt formed with   a mineral acid, preferably in the form of hydrochloride.   Process according to one of Claims 1 to 5,   characterized in that the reaction is carried out at 40 ° C, preferably at a temperature between 50 and 60 ° C.   7. Method according to one of claims 1 to 6,   characterized in that the reaction is carried out for 0.5 to 3 hours   hours, preferably for 1 to 2 hours.   8. Method according to one of claims 1 to 7,   for the preparation of 2 (E) - (p-chloro-phenylmethylene) / -   e (E) - (3-Diisopropylamino-propoxyimino) 7-cyclohexane,   terized by reacting 2-Z (E) - (p-chloro)   phenylmethylene) 7-cyclohexane-1-one- (E) -oxime with chlorine   1-diisopropylamino-3-chloro-propane hydrate.   9. Process according to claim 8, characterized in that the reaction is carried out in the mixture of water and   dimethylsulfoxide in the presence of sodium hydroxide and hy- potassium hydroxide.