GB2135994A - Process for the preparation of basic oxime ethers - Google Patents

Process for the preparation of basic oxime ethers Download PDF

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GB2135994A
GB2135994A GB08403234A GB8403234A GB2135994A GB 2135994 A GB2135994 A GB 2135994A GB 08403234 A GB08403234 A GB 08403234A GB 8403234 A GB8403234 A GB 8403234A GB 2135994 A GB2135994 A GB 2135994A
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oxime
general formula
reaction
preparation
process according
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GB2135994B (en
GB8403234D0 (en
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Zoltan Budai
Tibor Mezei
Aranka Lay
Lujza Petocz
Katalin Grasser
Eniko Szirt
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Egyt Gyogyszervegyeszeti Gyar
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Egyt Gyogyszervegyeszeti Gyar
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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

SPECIFICATION Process for the preparation of basic oxime ethers This invention relates to a new and improved process for the preparation of basic oxime ethers.
According to the present invention there is provided a process for the preparation of compounds of the general Formula I
and acid addition salts thereof /wherein R is a phenyl group optionally substituted by one to three halogen atom/s/ and/or lower alkoxy group/s/; R' and R2 each are hydrogen or together form a valence bond; A is lower alkylene; R3 and R4 each stand for hydrogen or lower alkyl or together with the adjacent nitrogen atom they are attached to form a 5-8-membered heterocylic 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/.
The compounds of the general Formula I are known and exhibit antidepressant, antiparkinson and local anaesthetic effect /Hungarian patent No. 169,298/. According to the said patent specification the compounds of the general Formula I may be prepared among others by condensing a compound of the general Formula II
with a compound of the general Formula Ill
in an inert solvent in the presence of a basic condensing agent /in which Formulae R, R1, R2, R3, R4 and n are as stated above/. In the examples of the said patent specification exclusively organic solvents /toluene, ethanol, benzene or xylene/ are usedsas inert solvent while sodium hydride, sodium amide and metallic sodium are applied as basic condensing agent.According to the said specification-without any experimental support alkali hydroxides can also be used as basic condensing agent and in this case water serves as solvent. According to the teaching of Hungarian patent specification No. 169,298 if alkali metals are used, an alcholic medium is suggested.
The above procedure disclosed in the said patent specification is encountered with serious difficulties, particularly on industrial scale production: -the halogeno alkyl amines of the general Formula Ill can only be used in the form of the free bases which are extremely unstable compounds being highly liable to dimerisation and polymerisation; -the specific capacity factor of the apparatus is unfavourable; -the reaction time is long /12-16 hours/; -the isolation of the end-product is carried out by complicated methods /decomposition of the sodium hydride or sodium amide, acidic and alkaline extractions, trans-precipitations etc./;; -the purification is accomplished by distillation in high vacuo which requires complicated and special equipment; -the gaseous hydrogen formed in the reaction constitutes explosion hazards and the evolved ammonia causes environmental pollution; -in certain cases isomerisation takes place in the reaction.
The latter drawback is shown by the fact that when 2-[/E/-/p-chlornphenylmethylenej-1 [/E/-/3'-diisopropylamino-propoxyimìno/]-cyclohexane is prepared according to Hungarian patent specification No. 169,298, in addition to the desired product a substance of unknown structure is formed in a significant amount which considerably differs in its physico-chemical parameters from the desired compound. The UV spectrum of the two products shows that while the Amax value of the desired compound is 280 nm /e = 17456.15/, the corresponding value of the unknown substance amount to Ajax 243 nm /e= = 1245/.
The said difference indicates that in the course of the reaction an undesired side-reaction /isomerisation/ took place.
Hungarian patent specification No. 169,298 relates to the preparation of pharmaceutically active new compounds. It was the object of the said patent specification to provide the new compounds in an amount sufficient for identification of the product and for the purposes of pharmacological tests. On the other hand, the object of the present invention is to provide a process for the preparation of the said known compounds of the general Formula 1 which is readily feasible on industrial scale production, too, eliminates the above disadvantages of the known methods and meets the requirments of environmental protection, energy savings and industrial economy.
According to the present invention there is provided a process for the preparation of basic oxime ethers of the general Formula I /wherein R is a phenyl group optionally substituted by one-three halogen atom/s/ and/or lower alkoxy group/s/; R1 and R2 each are hydrogen or together form a valence bond; A is lower alkylene;; R3 and R4 each stand for hydrogen or lower alkyl or together with the adjacent nitrogen atom they are attached to form a 5-8-membered heterocylic 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 by reacting an oxime of the general Formula ll with a halogeno compound of the general Formula Ill /wherein Hal stands for halogen and R, R', R2, R3, R4 A and n are as stated above/, which comprises carrying out the reaction of the oxime of the general Formula II and the halogeno compound of the general Formula Ill or an acid addition salt thereof in the simultaneous presence of a lower alkali alcoholate and an aromatic organic hydrocarbon and, if desired, converting the compound of the general Formula I thus obtained into an acid addition salt thereof in a known manner.
It has been found that when the reaction of the oxime of the general Formula II and the halogeno compound of the general Formula Ill or an acid addition salt thereof is carried out in the presence of an alkali alcoholate and an aromatic organic hydrocarbon, the reaction takes place within a short time with excellent yields and a product of high purity being free of isomers is obtained.
The term "lower alkoxy" used throughout the specification relates to straight or branched chained alkoxy groups having 1-4 carbon atoms /e.g. methoxy, ethoxy, n-propoxy, isopropoxy etc./. The term "halogen" encompasses the fluorine, chlorine, bromine and iodine atoms. The term "lower alkylene" relates to straight or branched chain alkylene groups having 2-4 carbon atoms /e.g. ethylene, trimethylene or 1 -methyl-ethylene/. The term "lower alkyl" relates to straight or branched chain alkyl groups having 1-4 carbon atoms /e.g. methyl, ethyl, n-propyl, isopropyl etc./.
The R3 and R4 groups together with the adjacent nitrogen atom they are attached to may form a 5-8 membered heterocyclic ring which may optionally contain a further oxygen or nitrogen atom and/or may be optionally substituted. The said heterocyclic group may be e.g. a morpholino, pyrrolidino, piperidino, N-methyl-piperazino, N-phenyl piperazino or N-benzylpiperazino group etc.
n represents preferably 4 or 5.
The acid addition salts of the compounds of the general Formula I may be pharmaceutically acceptable acid additions salts formed with inorganic or organic acids /e.g hydrochlorides, hydrobromides, sulfates, maleates, fumarates, acetates, lactates etc./.
According to the process of the present invention preferably sodium methylate, sodium ethylate, potassium methylate, potassium ethylate or potassium tertiary butylate may be used as alkali alcoholate. As aromatic organic hydrocarbon preferably benzene, toluene or xylene or a mixture thereof may be applied. According to a preferred embodiment of the present invention the compounds of the general Formula II and Ill may be reacted in the presence of sodium methylate and toluene, xylene or benzene.
The reaction may be carried out preferably under heating particularly at the boiling point of the reaction mixture. One may proceed preferably by distilling off the lower alkanol formed in the reaction together with an aromatic organic hydrocarbon. The reaction time is very short, the reaction is completed within one or two hours.
The starting material of the general Formula Ill may also be used in the form of an acid addition salt, preferably as an acid addition salt formed with an inorganic acid, particularly in the form of the hydrochloride thereof.
The reaction mixture may be worked up by methods known per se. Thus one may proceed by pouring the reaction mixture into water, washing and removing the solvent. According to an other alternative the compound of the general Formula I may be isolated in form of an acid addition salt thereof. Salt formation may be carried out by methods known per se by reacting with the corresponding acid in the inert solvent as medium.
According to a preferred embodiment of the present invention the following compounds may be prepared: 2-(/E/-phenylmethylene]-1 (/E/-/ 3'-diisopropylaminopropoxyimino/]-cyclohexane; 2-[/ E/-/p-chloro-phenylmethylene/]-1 -(/ E/-/3'-diisopropylaminopropoxy-imino/]-cyclohexane; 2-benzal-1 -/2'-diisopropylamino-ethoxyimino/-cycloheptane.
The advantage of the process of the present invention is that is is readily feasible on inudstrial scale production, too /short reaction time, simple isolation, elimination of complicated and special purification by distillation in high vacuo; no reactions of explosion hazards are used/, the side reactions are pushed back and a product of high purity is obtained by excellent yields.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to the said Examples.
Example 1 Preparation of 2-[/E/-/2',4-dichloro-phenylmethylene/l- -C/E/-/4'-benzyl-piperazinyl-propoxy- imino/J-cyclohexane Into an apparatus equipped with a stirrer 1 50 ml of anhydrous toluene, 5.4 g /0.01 mole/ of sodium methylate and 27.02 g /0.1 mole/ of 2-[/E/-/2',4-dichloro-phenylmethylene/]- cyclohexane-1 -one-/E/-oxime are weighed in. From the reaction mixture about 30 ml of a mixture of methanol and toluene are distilled off and a solution of 27.7 g /0.11 mole) of N benzyl-N'-/3-chloro-propyl/-piperazine in 50 ml of toluene is added under heating to boiling and the mixture is subjected to post-reaction for 1-2 hours.The reaction mixture is poured into 1 50 ml of icecold water, the toluene solution is washed neutral and the solvent is removed in vacuo. Thus 41.94 g of the desired product are obtained,yield 86.2%. The 2-/E/-butenedioate / 1/2/ melts at 197-200.5 "C.
Analysis: for the Formula C35H41Cl2N3O9 /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. Amxx =273nm/e=15409/.
Example 2 Preparation of 2-C/E/-/m-chloro-phenylmethylene/l-l -[/E/-/4"-benzyl-piperazinyl-ethoxyimi- no/]-cyclohexane Into an apparatus equipped with a stirrer 23.57 g /0.1 mole/ of 2-[/E/-/m-chloro phenylmethylene/]-cyclohexane-l-one-/E/-oxime, 1 50 ml of xylene and 18.9 g /0.35 mole/ of sodium methylate are weighed in and 30 ml of a mixture of xylene and methanol are distilled off under stirring and atmospheric pressure. The reaction mixture is cooled to a temperature below the boiling point and 34.2 g /0.11 mole/ of N-benzyl-N'-/2-chloroethyl/-piperazinedihydrochloride are added.The reaction mixture is heated to boiling for some hours while a further 50 ml of solvent are distilled off, the mixture is heated to boiling for some hours, then cooled to 20 "C and poured into 200 ml of icecold water. The xylene phase is washed neutral with water and evaporated in vacuo. Thus 38.25 g of the desired compound are obtained, yield 87.3%.
The 2-/E/-butenedioate /1/2/ melts at 197-199.5 "C.
Analysis: for the Formula C34H40CIN304 /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 = mxx =2 74nm/=15246/.
Example 3 Preparation of 2-/ E/-phenylmethylene- 1 -(/ E/-4'-phenyl-piperazinyl-propoxyimino]-cyclohexane One proceeds as described in Example 1 except that 20.1 9 /0.1 mole/ of 2-/E/phenylmethylene-cyclohexane-1-one/E/-oxime and 25.0 g /0.105 mole/ of N-phenyl-N'-/3- chloropropyl/-piperazine are used, 35.19 g of the desired compound are obtained, yield 87.2%. The hydrochloride melts at 190-194 C.
Analysis: for the Formula C26H34CIN3O /440.04/ Calculated: C 70.97 /a H 7.79% Cl 8.06% N 9.55% Found: C 71.06% H 7.83% Cl 8.11% N 9.61% Example 4 Preparation of 2-[/ E/-/ o-chloro-phenylmethylene/]-1 -F/ E/-/4'-benzyl-piperazinyl-propoxyimi- no/J-cyclohexane The process according to Example 2 is carried out except that 23.57 g /0.1 mote/ of 2-/E/ /o-chloro-phenylmethylene/-cyclohexane-1-one-/E/-oxime and 35.72 g /0.11 mole/ of N benzyl-N7-i 3-chloropropyl/-piperazine-d ihydrochloride are used as starting material. Thus 37.71 g of the desired compound are obtained, yield 83.4%.
The 2-/E/-butenedioate /1/2/ melts at 197-201 C.
Analysis: for the Formula C35H42ClN3O4 /603.5/ Calculated: 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. AmaX= = Ama =269nm/=1I573/.
Example 5 Preparation of 2-/ E/-phenyl methylene- 1 -/E/-/41-benzyl-piperazinyl-ethoxy-imino/J-cyclohep- tane One proceeds according to Example 1 except that 21.53 g /0.1 mole/ of 2-/E/phenylmethylene-cycloheptane-1-one-/E-oxime and 26.16 g /0.11 mole/ of N-benzyl-N'-/2chloroethyl-piperazine are used as starting material. Thus 38.8 g of the desired compound are obtained, yield 93.2%.
The dihydrochloride melts at 206-209 C.
Analysis: for the Formula C27H36ClN3O /489.62/ Calculated: 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.: Amax 262 nm /e = 17012/ Example 6 Preparation of 2-/ E/-phenylmethylene-1 -1/ E/-/3'-diisopropylamino-propoxyimino/]-cyclohexane One proceeds according to Example 1 except that 20.13 g /0.1 mole/ of 2-/E/ phenylmethylene-cyclohexane-1-one-/E/-oxime and 19.53 g /0.11 mole/ of 1-diisipropylam- ino-3-chloro-propane are used as starting material. Thus 33.05 g of the desired compound are obtained, yield 96.5%.
The 2-/E/-butenedioate /1/1/ melts at 130-132 C.
Analysis: for the Formula C26H38N2OS /458.61/ Calculated: C 68.09% H 8.35% N 6.10% Found: C 67.95% H 8.42% N 6.03% UV.:Amax = 275 nm Example 7 Preparation of 2-/E/-/p-chlorn-phenylmethylene/]-1 -(/ E/-/ 3'-diisopropylamino-propoxyimi- no/J-cyclohexane One proceeds according to Example 1 except that 23.6 9 /0.1 mole/ of 2-[/E/-p-chlorophenylmethylene]-cyclohexane-1-one-/E/-oxime and 19.54 g /0.11 mole/ of 1-diisopropylamino-3-chloro-propane are used as starting material. Thus 37.14 g of the desired compound are obtained, yield 98.5%.
The 2-/E/-butenedioate /1/1/ melts at 87-89.5 C.
Analysis: for the Formula C26H37ClN2Oj /493.06/ Calculated: 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.: Amax =280nm/e=17456/ Example 8 Preparation of 2-/Z/-phenylmethylene- 1 -(/ 2'-diisopropylamino-etjoxyimino/J-cycloheptane The process according to Example 2 is carried out except that 21.53 g /0.1 mole/ of 2-/Z/phenylmethylene-cycloheptane-1-one-/E/-oxime and 22.02 g /0.11 mole/ of 1-dimethylamino2-chloro-ethane-hydrochloride are used as starting material. Thus 31.3 9 of the desired product are obtained, yield 91.4%.
The 2-/E/-butenedioate /1/1/ melts at 117-120 "C.
Analysis: for the Formula C26H38N2O5 /458.6/ Calculated: C 68.09% H 8.35% N 6.11% Found: C 67.92% H 8.42% N 6.07% UV.: Amax 258 nm / = 11182/ Example 9 Preparation of 2-[/ E/-/p-chlorn-phenylmethylene/i- 1 -E/ E/-/2'-dimethylamino-ethoxyimino/]- cyclohexane One proceeds according to Example 1 except that 23.57 9 /0.01 mole/ of 2-[/E/-/p-chlorophenylmethylene/]-cyclohexane-1-one-/E/-oxime and 12.24 9 /0.15 mole/ of 1-dimethylamino-2-chloro-ethane are used as starting material. Thus 28.60 9 of the desired product are obtained, yield 93.2%.
The 2-/E/-butene-dioate /1/1/ melts at 168.5-171 "C.
Analysis: for the Formula C2,H27CIN205 /422.92/ Calculated: C 59.64% H 6.44% Cl 8.38% N 6.62% Found: C 59.42% H. 6.38% Cl 8.27% N 6.67% UV. Amxx = 275 nm /e = 19292/ Example 10 Preparation of 2-benzyl-1 -L/ E/-/2'-dimethylamino-ethoxyimino/J-cycloheptane One proceeds according to Example 2 except that 21.63 9 /0.1 mole/ of 2-benzyl cycloheptane-1-one-/E/oxime and 16.84 9 /0.11 mole/ of 2-dimethylamino-1-chloro-ethane- hydrochloride are used as starting material. Thus 26.96 9 of the desired product are obtained, yield 93.5%.
The 2-/E/-butenedioate /1/1/ melts at 121 "C.
Analysis: for the Formula C22H32N2O5 /404.51/ Calculated: C 65.32% H 7.97% N 6.93% Found: C 65.47% H 7.82% N 6.95% Example 11 Preparation of 2-/ E/-phenylmethylene-1 -[/ E/-/41-methyl-pipernzinyl-prnpoxyimino/cyclohep- tane One proceeds according to Example 1 except that 21.25 9 /0.1 mole/ of 2-/E/phenylmethylene-cycloheptane-1-one-/E/-oxime and 18.55 9 /0.15 mole/ of N-methyl-N'-/'chloropropyl/-piperazine are used as starting material and toluene is replaced by benzene. Thus 34.67 9 of the desired compound are obtained, yield 93.8%.
The 2-/E/-butenedioate /1/2/ melts at 204-208 "C.
Analysis: for the Formula C31H43N30g /601.71/ Calculated: C 61.88% H 6.98% N 7.20% Found: C 61.62% H 6.87% N 7.17% UV. Amax = 272 nm /e= 1370/ Example 12 Preparation of 2-/ E/-phenylmethylene- 1 -[/ E/-/ 2'-dimethylamino-ethoxyimino/3-cycloheptane One proceeds according to Example 2 except that 21.53 9 /0.1 mole/ of 2-/E/ phenylmethylene-cycloheptane-1 -one-/ E/-oxime and 18.7 9 /0.105 mole/ of 1-diethylamino-2 chloro-ethane-hydrochloride are used as starting material and xylene is replaced by toluene.
Thus 27.51 9 of the desired compound are obtained, yield 87.5%.
The 2-/E/-butenedioate /1/1/ melts at 86-88 "C.
Analysis: for the Formula C24H34N2O5 /430.53/ Calculated: C 66.95% H 7.96% N 6.51% Found: C 67.12% H 8.04% N 6.58% UV. Amax =264nm/e=16395/ Example 13 Preparation of 2-/ E/-phenylmethylene-1-]/ E/-/ 2'-diisopropylamino-ethoxyimino/]-cyclohexane One proceeds according to Example 1 except that 20.13 9 /0.1 mole/ of 2-/E/ phenylmethylene-cyclohexane-1 -one-/E/-oxime and 1 8.00 9 /0.11 mole/ of 1 -diisopropylamino-2-chloro-ethane are used as starting material. Thus 31.71 9 of the desired compound are obtained, yield 96.3%.
The 2-/E/-butenedioate /1/1/ melts at 103-105 "C.
Analysis: for the Formula C25H36N2O5 /444.58/ Calculated: C 67.54% H 8.16% N 6.30% Found: C 67.23% H 8.32% N 6.28% UV.:Amax 275 nm /e = 17304/ Example 14 Preparation of 2// E/-phenylmethylene- 1 -[/ E/-/ 3'-dimethylamino-propoxyimino/]-cyclooctane One proceeds according to Example 1 except that 22.93 9 /0.1 mole/ of 2-/E/ phenylmethylene-cyclooctane-1-one-/E/-oxime and 15.11 9 /0.11 mole/ of 1-dimethylamino- 3-chloro-propane are used as starting material and the toluene is replaced by benzene. Thus 28.40 g of the desired compound are obtained, yield 94.5%.
The 2-/E/-butenedioate /1/1/ melts at 136-139 "C.
Analysis: for the Formula C23H32N2O5 /416.52/ Calculated: C 66.32% H 7.75% N 6.73% Found: C 65.89% H 7.64% N 6.79% UV.: Amax 276 nm /e = 14395/ Example 15 Preparation of 2-/ E/-phenylmethylene-1 -[/ E/-/ 2'-dimethylamino-21-methyl-ethoxyimino/]-cy- clohexane One proceeds according to Example 1 except that 20.13 g g /0.1 mole/ of 2-/E/phenylmethylene-cyclohexane-1 -one-/ E/-oxime and 16.6 g /0.105 mole/ of 2-dimethylamino2-methyl-1-chloro-ethane are used as starting material. Thus 26.9 9 of the desired compound are obtained, yield 93.9%.
The 2-/E/-butenedioate melts at 113-117 C.
Analysis: for the Formula C22H30N2O5 /402.48/ Calculated: C 65.64% H 7.51% N 6.96% Found: C 65.42% H 7.39% N 6.87% UV.: Amax 273 nm / = 13475/ Example 16 Preparation of 2-/ E/-phenylmethylene- 1 -[ E/-/2'-dimethylamino-21-methyl-ethoxyimino/]-cy- cloheptane One proceeds according to Example 1 except that 21.53 g /0.1 mole/ of 2-/E/ phenylmethylenecycloheptane-1-one/E/-oxime and 16.6 g /0.105 mole/ of 2-dimethylamino 2-methyl-1-chloro-ethane are used as starting material. Thus 28.61 g of the desired compound are obtained, yield 95.2%.
The 2-/E/butenedioate /1/1/ melts at 120-123 C.
Analysis: for the Formula C23H32N2O5 Calculated: C 66.32% H 7.75% N 6.73% Found: C 66.18% H 7.62% N 6.65% UV. Amax = 262 nm/s = 17595/ Example 17 Preparation of 2-/ E/-phenylmethylene- 1 -E/ / 2 E/-/ 2'-diisopropylamino-ethoxyimino/]-cyclooctane One proceeds according to Example 1 except that 22.93 9 /0.01 mole/ of 2-/E/phenylmethylene-cyclooctane-1-/E/-oxime and 22.02 g /0.11 mole/ of 1-diisopropylamino-2chloro-ethane are used as starting material. Thus 33.22 g of the desired compound are obtained, yield 93.3%.
The hydrochloride melts at 158-161 C.
Analysis: for the Formula C23H37CIN20 /393.0/ Calculated: 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. Amax = 276 nm /e = 14170/ Example 18 Preparation of 2-[/ E/-/ p-chloro-phenylmethylene/]-1 -[/ E/-/4'-methyl-piperazinyl-propoxyimi- no/J-cyclohexane One proceeds according to Example 1 except that 23.57 g /0.1 mole/ of 2-/E/-/p-chloro phenylmethylene/-cyclohexane-1-one-/E/-oxime and 18.55 g /0.105 mole/ of N-methyl-N' /3-chloropropyl/-piperazine are used as starting material and toluene is replaced by xylene.
Thus 34.49 g of the desired compound are obtained, yield 87.6%.
The 2-/E/-butenedioate /1/2/ melts at 196-199 C.
Analysis: for the Formula C29H38ClN3O9 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% UV.: Amax 278 nm /e = 16507/ Example 19 Preparation of 2-[/E/-/m/chloro-phenylmethylene/]- 1 -[/ E/-/4'-benzyl-piperazinyl-propoxyimi- no/]-cycloheptane One proceeds according to Example 2 except that 24.97 g /0.01 mole/ of 2-[/E/-/m chloro-phenylmethylene/]-cycloheptane-1-one-/E/-oxime and 35.72 9 /0.11 mole/ of N benzyl-N'-/3-chloropropyl/-piperazine-dihydrochloride are used as starting material. Thus 39.02 g of the desired compound are obtained, yield 86.5%.
The 2-/E/-butenedioate 1/2/ melts at 196-198 "C.
Analysis: for the Formula C35H42ClN3O9 /684.20/ Calculated: 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.:Amax= 274 nm =2 74nm/s=13700/

Claims (11)

1. Process for the preparation of basic oxime ethers of the general Formula I
/wherein R is a phenyl group optionally substituted by one to three halogen atom/s/ and/or lower alkyl group/s/; R1 and R2 each are hydrogen or together form a valence bond; A is lower alkylene; R3 and R4 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 by reacting an oxime of the general Formula II
with a halogeno compound of the general Formula Ill
/wherein Hal stands for halogen and R, R1, R2, R3, R4, A and n are as stated above/, which comprises carrying out the reaction of the oxime of the general Formula II and the halogeno compound of the general Formula Ill or an acid addition salt thereof in the presence of a lower alkali alcoholate and an aromatic organic hydrocarbon, and if desired, converting the compound of the general Formula I thus obtained into an acid addition salt thereof in a known manner.
2. Process according to Claim 1, which comprises using sodium methylate, sodiym ethylate, potassium methylate, potassium ethylate or potassium tertiary butylate as alkali alcoholate.
3. Process according to Claim 1 or 2, which comprises using benzene, toluene or xylene or a mixture thereof as aromatic organic hydrocarbon.
4. Process according to any of Claims 1-3, which comprises carrying out the reaction under heating, preferably at the boiling point of the reaction mixture.
5. Process according to any of Claims 1-4, which comprises carrying out the reaction for 1-2 hours.
6. Process according to any of Claims 1-5 for the preparation of 2-[/E/-phenylmethylene]- 1 -/ E/-/ 3'-diisopropylam ino-propoxyimino /]-cyclohexane by reacting 24/E/-phenylm,ethylene]- cyclohexane-1 -one-/E/-oxime with 1 -diisopropylamino-3-chloro-propane, which comprises carrying out the reaction in the presence of sodium methylate and toluene.
7. Process according to Claim 1 for the preparation of 2-[/E/-/p-chloro-phenylmethylene/]- 1-[/E/-/3'-diisopropylamino-propoxyimono/]-cyclohexane by reacting 2-[/ E/-/p-chloro-phenyl- methylene/]-cyclohexane- 1 -one-/ E/-oxime with 1 -diisopropylamino-3-chloro-propane, which comprises carrying out the reaction in the presence of sodium methylate and toluene.
8. Process according to Claim 1 for the preparation of 2-benzal-1-/2'-diisopropylamino- ethoxyimino/-cycloheptane by reacting 2-benzal-cycloheptanone-oxime with 2-diisopropylaminoethyl-chloride, which comprises carrying out the reaction in the simultaneous presence of sodium methylate and toluene.
9. Process according to any of Claims 1-8, which comprises distilling off the alcohol formed in the reaction together with the aromatic organic hydrocarbon.
10. A process substantially as hereinbefore described in any one of Examples 1 to 1 9.
11. A basic oxime ether made by a process as claimed in any one of claims 1 to 10.
GB08403234A 1983-02-08 1984-02-07 Process for the preparation of basic oxime ethers Expired GB2135994B (en)

Applications Claiming Priority (1)

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HU83415A HU189226B (en) 1983-02-08 1983-02-08 Process for producing basic oxime-ethers

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GB8403234D0 GB8403234D0 (en) 1984-03-14
GB2135994A true GB2135994A (en) 1984-09-12
GB2135994B GB2135994B (en) 1986-08-20

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AT (1) AT385508B (en)
BE (1) BE898834A (en)
CH (1) CH659063A5 (en)
DE (1) DE3404424A1 (en)
ES (1) ES529566A0 (en)
FR (1) FR2540492B1 (en)
GB (1) GB2135994B (en)
HU (1) HU189226B (en)
IT (1) IT1196016B (en)
SU (1) SU1299502A3 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0168245A2 (en) * 1984-07-10 1986-01-15 Egis Gyogyszergyar Basic oxime ethers, pharmaceutical compositions possessing antianginal activityand the use of basic oxime ethers for manufactoring medicaments for the treatment of angina
EP0388977A2 (en) * 1989-03-23 1990-09-26 Warner-Lambert Company Polycyclic amines useful as cerebrovascular agents
US5276053A (en) * 1989-03-23 1994-01-04 Warner-Lambert Company Polycyclic amines useful as cerebrovascular agents

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU202195B (en) * 1987-12-31 1991-02-28 Egyt Gyogyszervegyeszeti Gyar Process for producing new substituted styrene derivatives and medical compositions comprising such compounds
HU212415B (en) * 1989-08-25 1996-06-28 Egyt Gyogyszervegyeszeti Gyar Process for producing new cyclic oxym derivatives and pharmaceutical compositions containing them as active components

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK149043C (en) * 1976-01-27 1986-05-26 Egyt Gyogyszervegyeszeti Gyar METHOD OF ANALOGUE FOR THE PREPARATION OF 2-BENZAL OR 2-BENZYL-1- (AMINOALCOXYIMINO) -CYCLOALKANES OR SALTS OR QUATERNARY AMMONIUM DERIVATIVES THEREOF
US4083978A (en) * 1976-01-27 1978-04-11 Egyt Gyogyszervegyeszeti Gyar Oxime ethers
HU178518B (en) * 1978-12-19 1982-05-28 Egyt Gyogyszervegyeszeti Gyar Process for preparing cyclododekanone oxime ethers

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0168245A2 (en) * 1984-07-10 1986-01-15 Egis Gyogyszergyar Basic oxime ethers, pharmaceutical compositions possessing antianginal activityand the use of basic oxime ethers for manufactoring medicaments for the treatment of angina
EP0168245A3 (en) * 1984-07-10 1987-04-29 Egis Gyogyszergyar Pharmaceutical compositions of antianginal activity
EP0388977A2 (en) * 1989-03-23 1990-09-26 Warner-Lambert Company Polycyclic amines useful as cerebrovascular agents
EP0388977A3 (en) * 1989-03-23 1991-07-31 Warner-Lambert Company Polycyclic amines useful as cerebrovascular agents
US5276053A (en) * 1989-03-23 1994-01-04 Warner-Lambert Company Polycyclic amines useful as cerebrovascular agents

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FR2540492B1 (en) 1988-02-19
CH659063A5 (en) 1986-12-31
AT385508B (en) 1988-04-11
DE3404424A1 (en) 1984-08-16
SU1299502A3 (en) 1987-03-23
ES8506605A1 (en) 1985-08-01
HU189226B (en) 1986-06-30
IT1196016B (en) 1988-11-10
BE898834A (en) 1984-08-03
ES529566A0 (en) 1985-08-01
FR2540492A1 (en) 1984-08-10
GB2135994B (en) 1986-08-20
ATA38784A (en) 1987-09-15
JPS59172453A (en) 1984-09-29
GB8403234D0 (en) 1984-03-14
IT8419469A0 (en) 1984-02-07

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