DE1795145A1 - Process for the preparation of succinimide derivatives - Google Patents

Description

Patent attorneys Dr. LOTTERHOS, Dr.-Ing.

6000 Frankfurt a. M. Annastrafje 19

1795U5

H. AU6.1968

Chinoin GySgyszer 4s Vegyfcszeti Termekek Gyara EI, Budapest ITT, Τδ utca 1-5 »Hungary

VBEOTAHBEN PREPARATION OF SUCCINIMIDE DERIVATIVES

The invention relates to a new method Inhibition of succinlmld derivatives.

Ia main patent Mr. G 30 236lYd / 12p, P 1W59o..4 vlxd a process for the production of the SucciniMid-Derlvat · the general formula

77/127 old

- ^X - ORIGINAL INSPECTED

109885/1627

Ii "* C ■■ · CHo

II ² ο = c .c «ο _T

described, wherein Έτ is hydrogen, aryl, aralkyl, alkyl or a heterocyclic radical; B ² denote aryl, aralkyl, alkyl or a heterocyclic radical, or the two or R alkyl groups together with the carbon atom to which they are attached form a carbocyclic system and A stands for a disubstituted amino group. The compounds of the formula I. and their acid addition additives can be used in pharmacy, in particular for the treatment of epilepsy.

According to the main patent no. O 30 236, the compounds of the formula I. are prepared by aan a compound of the general formula

0-00-0 III.

where B * and B ^{2 have} the above meaning, a Mannioh-

Subject to reaction.

This known method has the disadvantage in that the products obtained have to be purified by crystallization before they can be used in pharmaceuticals.

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The processing of the reaction mixture is often part of the operation Difficulties associated with it, namely in most cases vacuum distillation is necessary. The aim of the invention is to devise an improved method which eliminates the above problems and the production of very pure end products.

The subject of the invention is as a further development of the main patent Hr. C 350 256 claimed a process for the preparation of compounds of the general formula

R ² R ¹ - C - CH ₉

o = cb = o. _T

CH ₂ -A.

and their salts, in which Έτ is hydrogen, aryl, aralkyl, alkyl

or a heterocyclic radical; ·

R ^{2 is} aryl, aralkyl, a heterocyclic radical or alkyl

mean, where the two Hr and R alkyl groups together.

with the carbon atom to which they are attached can form carbocyclic system;

A stiffens for a straight-chain or cyclic secondary amine,

characterized in that one

a) a compound of the uncommon formula

f R ¹ - C - CH ₂ .

ö «C _n ^ Jo .o ■ n.. ■

CH ₂ -X

109885/1927

wherein R ^ and R have the above meanings and X is a hydroxyl group, a halogen atom or a group of the formula -O-acyl means, reacts with secondary amines; or b) a compound of the general formula

E ¹ - C - CH ₅
II ²
O = C CsO III.

wherein Ir and R has the above meaning, with a compound of the general formula

R ^5-0 -CH ₂ -A IV.

reacts, wherein R * is an alkyl or aralkyl group and A has the above meaning,.

uQ-i, if desired, converts the compounds thus obtained into acid addition salts and, if appropriate, the compounds of the formula I. or their salts mixed with suitable inert pharmaceutical carriers.

By "alkyl groups" are those straight chain or branched hydrocarbon radicals with advantageously 1-6 carbon atoms, such as methyl, ethyl, Propyl, isobutyl group and the like. These alkyl groups can optionally contain one or more of the following substituents: alkyl, alkoxy, hydroxy, halogen, nitro or amino. The term "aralkyl group ** denotes alkyl groups of 1-3 carbon atoms in which one hydrogen atom is substituted by an aryl radical (e.g. Benzyl or ß-phenethyl). The aryl group of the aralkyl radical

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S 1795H5

kals can itself carry one or more sub-bits, e.g. alkyl, alkoxy, hydroxy, halogen, nitro or amino group. The term "yeast yeast radical" denotes advantageously 5 or 6 membered monocyclic heterocyclic Groups that contain at least one oxygen, nitrogen and / or contain sulfur atom. As such groups are the the following heterocyclic radicals are particularly preferred? Morpholyl, pyridyl, piperidyl, piperazinyl and thiazolyl.

The symbol "A" advantageously denotes an aryl, aralkyl or heterocyclic ring which is attached to the aromatic or heterocyclic ring may be substituted. ^ A is advantageously a dialkylamino, piperazinyl, Indolyl, piperldyl, ephedrinyi, or a morpholinyl group. These groups can optionally be substituted e.g. by alkyl, alkoxy, or halogen groups. The heterocyclic radicals can have aromatic substituents wear.

According to a particularly advantageous embodiment of the process according to the invention, R represents alkyl, especially methyl; R for aryl, especially phenyl, and A for λ a morpholinyl group.

According to the method a) of the invention

TT -L . -

drive «are compounds of the formula with secondary amines implemented. X can be a radical of the formula -O-acyl, wherein the acyl radical is on aliphatic carboxylic acids (e.g. Acetic acid); aromatic carboxylic acids (e.g. benzoic acid) aliphatic sulfonic acids (e.g. methanesulfonic acid) or aromatic sulfonic acids (e.g. benzöl sulfone acid or to-

BATH 109885/1927

luolaulfonic acid) can be derived. AIa secondary amines can advantageously dialkylamines, such as dimethylamine, diethylamine uBw, or morpholine, piperazine, indole or piperidine can be used. ......

If compounds of the formula II are used, in which X oiae denotes a hydroxyl group, can the reaction is advantageous in the presence of alcohol Boiling point of the reaction mixture. the Implementation takes place within 1-2 hours and will be effective achieved excellent yields. After concentrating and cooling the solution, a pure, crystalline product is obtained, so that further purification steps are not necessary. A highly pure product is obtained by distilling off most of the solvent and the Solution cools down in the presence of pure alcohol «

Should the Haiogeurnethy! Compounds of the formula II. Are used (X stands for halogen, especially for chlorine), the reaction is carried out in the presence of an acid binder (e.g. triethylamine) advantageously carried out in an apolar solvent such as benzene as the medium. Before working up the precipitated triethylamine halohydrate is removed from the reaction mixture by filtration.

According to method b) of the process according to the invention, compounds of the formula III are reacted with compounds of the formula IV. In the formula III, Ir is advantageously an alkyl group with 1-6 carbon atoms or a bensyl group or β- phenethyl group. The symbol A advantageously denotes a Dlalkylamlno, indolyl,

BATH ORIGINAL

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Piperidyl, piperazinyl, ephedrinyl, or morphclinyl radical, Die-Ba Radicals can optionally carry one or more substituents such as alkyl, alkoxy, halogen and phenyl groups.

The reaction is preferably carried out in the presence of a Water in the form of a solvent (e.g. benzene and the same). The reaction can be accelerated by heating.

The solvent can be used for working up the reaction mixture distill off the still warm solvent, for example oily residue containing a gana small bark (| Add methanol »After the mixture has cooled down, it becomes a very pure Obtained product which can be used in pharmacy without further purification.

The compounds of the formula I. can be converted into acid addition salae. Inorganic acids (e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, boric acid) or organic acids (e.g. acetic acid, formic acid, succinic acid, etc.) can be used to form salts. The salt formation is carried out in manner known per se, for example by λ addition of an equimolar amount of the corresponding acid of Löaunf formed with an organic solvent the base of the formula I.

The resulting compounds of the formula I. and their acid addition salts al3 medicaments can be found in the form of pharmaceutical preparations which use this compound as active Component mixed with suitable pharmaceutical, organic or contain inorganic carrier material. Suitable

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BAD ORIGINAL 109885/1927

Carriers are, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum, polyalkylene glycol, vasellh, etc. The pharmaceutical preparations can be in solid form (e.g. as tablets, coated tablets, suppositories, capsules) or in in liquid form (e.g. as solutions, suspensions or emulsions) - If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, stabilizers, agitation or emulsifiers, salt to change the osmotic pressure, or buffers. You can also use others therapeutically contain valuable substances.

The advantage of the method according to the invention is that that it is the compounds of formula I. in very pure, suitable for pharmaceutical use directly without ^ purification State supplies.

The following examples are intended to illustrate the process according to the invention, but are not intended to represent any restriction thereof.

Example It

6.57 g of N-methylol-oC-phenyl- «- methyl-suoolnimide are dissolved in 20 ml of anhydrous ethanol, whereupon a solution of 2.65 g of morpholine and 5 ml of ethanol is added. The mixture is refluxed for 2 hours. After concentrating the reaction mixture, the residue is left to crystallize in the presence of a small amount of ethanol. 6.75 g of cC-phenyl-of-methyl-N- ( morpholinyl-m ethyl) -suooinimide are obtained. Melting point 69-7O ⁰ C. Example 2t 2.12 g of N-chloromethyl-oC-phenyl-oC-methyl-suooinirald are in

109885/1927 ORIGINAL BATHROOM

1795U5

20 ηα benzene dissolved. A solution of 2.65 g of morpholine in 5 ml of benzene and a solution of 3.05 g of triethylamine in 5 ml of benzene are added in parallel at room temperature. The reaction mixture is heated to reflux. The precipitated triethylamine chlorohydrate salt is filtered and the benzene solution is concentrated. The residue is left cold in the presence of a small slope of ethanol to crystallize. 6.2 g of the oC-phenyl-oC-methyl-N- (morpholinyl-methyl) -succinimlde are obtained. Melting point: 68-70 ⁰ C.

Example 3t ^

4-35 g of Hörpholinyl-methyl-ethyl-ether and 10 ml of benzene are added to a solution of 5.67% phenyl-tf-methyl-sucoinimide and 25 ml of benzene. The mixture is refluxed for 2 hours. After concentration the residue is left cold in the presence of a small amount of ethanol to crystallize. 6.3 g of the oC-phenyl-oC-methyl-N- (morpholinyl-methyl)> - aruccinimida are obtained. Melting point: 68 * 70 ° C. Analysis * N % * 9.73 (calc .: 9.72) Ash content: 0.04 % * Example 4:

6.15 g of eC-phenyl-N-methylol-sucoinimld are dissolved in 25 ml of water

dissolved free ethanol, whereupon a solution of 2.67 g of morpholine be added in 5 ml of ethanol. The mixture is refluxed for 2 hours, after which the reaction mixture is concentrated. The residue is left to breath for one night in the refrigerator. The resulting crystalline <K-Phenyl-N- - (morpholinyl-methyl X-auocinimide melts at 115-117 ° C. (6.02 g).

109885/1927

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Example 5:

5.49 g of N-Ifethylol-oC-ethyl-oC-raethyl-sucoinlmid are dissolved in 15 ml of anhydrous ethanol, whereupon a solution of 2.67 g of morpholine and 5 ml of ethanol is added. The mixture is refluxed for 2 hours and concentrated. After standing in the cold, the residue crystallizes. The crystals are filtered and washed. 4.72 g (-Aethyl-oC-methyl-N- (morpholinyl-methyl) ·: suooinimide are obtained. Melting point »53-55 ° 0. Example 6;
^ 5.13 g of N-Hfethylol-oC-spiro-tetramethylene-succinimide are dissolved in 25 ml of anhydrous ethanol, whereupon a solution of 2 »67 g of morpholine and 5 ml of anhydrous ethanol is added. The reaction mixture is left to stand for 2 hours. After concentration, the residue is worked up as described in Example 4. 4.33 g of the oC-spirotetramethylene-N- (morpholinyl-methyl) -8ucclnimide are obtained · Melting point: 84-86 ° C.
Example 7:

6.42 g of cC-Morpholinyl ^ N-methylol-auooinimid are in 27 ml * Dissolved anhydrous ethanol. The solution will be 2.67 g '

Morpholine dissolved in 5 ml of anhydrous ethanol was added. The mixture is refluxed for 2 hours and concentrated. The residue is worked up in the manner described in Example 4. 6.18 g of cC-morpholnyl-N- - (Morpholinyl-methyl) -succinimide obtained. Melting point » 106-107 ° C.

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1795U5 H. '

Example 8:

6.36 g oC-piperidyl-N-methylol-succinimide are in 30 nil Dissolved anhydrous ethanol, whereupon a solution of 2.67 g Morpholine and 5 nil anhydrous ethanol are added. That The mixture is refluxed for 2 hours and concentrated. The residue is worked up as described in Example 4. There are 5.93 g of the of-Piper idyl-N- (morpholinyl- methyl) succinimides. Melting point: 116-118 ° C, Example 9:

4.35 g of morpholinyl methyl ethyl ether and 10 ml of benzene are ^ j

a solution of 5.25 g oC-phenyl-succinimide and 30 ml benzene admitted. The mixture is refluxed for 2 hours and then narrowed. The residue is left to stand in the refrigerator for one night in the presence of a small amount of ethanol. The precipitated crystals are filtered and washed. 6.1 g of the oC-phenyl-N- (morpholinyl-methyl) - -succinimide obtained »Melting point: 115-117 ° C. Example 10:

4 »35 g of morpholinyl methyl ethyl ether and 10 ml of benzene are used a solution of 4.23 g oC-ethyl-o ^ -methyl-suocinimide and 25 ml of benzene was added. The mixture is refluxed for 2 hours and then concentrated by distillation. To the A small amount of ethanol is added to the residue, whereupon the mixture is left to stand in the refrigerator for one night. The precipitated crystals are filtered and washed. It will 5.95 g of the oC-ifethyl-oC-ethyl-N- (morpholinyl-raethyl) - -succinimide obtained. Melting point: 53-55 ° C.

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109885/1927

it

Example 11 j

1795 U 5

4.35 g of morpholinyl methyl ethyl ether and 10 ml of benzene are used a solution of 4 »59 g oC spiro-tetraioethylene sueoiniinid and 30 ml of benzene are added, whereupon the mixture is refluxed for 2 hours. After concentrating the mixture a small amount of acetone is added to the residue · Ea is left in the refrigerator for one night * The excreted Crystals are filtered and washed · There are 5 * 63 g of cC-spiro-tetramethylene-N-cmorpholinyl ^ inethyl) -. -succinimide obtained. Melting point: 84-86 ° 0 -

Example 12:

4.35 g of morpholinyl methyl ethyl ether and 10 ml of anhydrous benzene are added to a solution of 5.52 g of oC-mbrpholinyl succinimide and 25 ml of benzene. The mixture is refluxed for 2 hours, whereupon the solvent is distilled off and a small amount of ethanol is added to the residue. The mixture is left to stand in the refrigerator for one night, after which the precipitated crystals are filtered and washed. 6.73 g of the oC-morpholinyl-N- (morpholinyl-methyl) -succinimide are obtained. Melting point: 106-107 ° C
Example 13:

4.35 g of morpholinyl methyl ethyl ether and 10 ml of benzene are added a solution of 5.46 g oC-piperidyl-suooinimid and 20 ml benzene admitted. The reaction mixture will stand for 2 hours calmly. After the solvent has been distilled off, the precipitated crystals filtered and washed. It will 6.48 g of the <X-piperidyl-N- (morpholinyl * -methyl) TSUC-cinimide were obtained. Melting point: 116-118 ° C.

1 0 9 8 * 8 5/1 9 2 7

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Claims (10)

PATENT CLAIM ' 1. As a further development of the process according to the main patent no.c.30 236, a process for the preparation of compounds of the general formula H ² R ¹ - 0 - CIU _T CH ₂ CH ₂ -A and their salts . Ä R is hydrogen, aryl, aralkyl, alkyl or a heterooyoli- so radical} R is aryl, aralkyl, a heterocyclic radical or alkyl interpret, where the two R and R alkyl groups together with. the carbon atom to which they are attached is an oarbo can form cyclic system; A stands for a straight-chain or cyoliohes secondary amine, characterized in that one a) a compound of the general formula R ^{2 H, 1} - 0 - OH. II ² n. 0 * C ß »0 V I. OHj-X 1 ο wherein R and R have the above meaning and X is a hydroxyl group, a halogen atom or a group of the formula -O-Aoyl, reacts with secondary amines} or 10a885 / 1927 b) a compound of the general formula H ² 1795U5 R ¹ • C - GH ₀ ι r ^m 0 »0 C« 0 1 '2 where R and R retain the above meaning, with a compound of the general formula. R ³ - O - CH ₂ - A IT. converts, wherein R is an alkyl or aralkyl group and A has the above meaning,. and mentioned, if the compounds obtained in this way are converted into structural addition salts and, if appropriate, the compounds of the formula I. or their salts mixed with suitable inert pharmaceutical carriers, 2. The method according to Claim 1, characterized in that. that compounds are used as starting material in which R is hydrogen, an optionally substituted monooyoliaohe aryl group, an optionally substituted aralfcyl group whose alkyl chain contains 1-3 carbon atoms, a 5- or 6-membered monooyolic heterooyolic group with 1- or 2 nitrogen, oxygen and / or sulfur atoms, or an alkyl group with ^{1-6 carbon atoms, R 2 is} an optionally substituted monooyolinohearyl group, • ■ ■ an optionally substituted aralkyl group, the alkyl chain of which has 1-3 carbon atoms, a 5- or 6-membered monooyolisohe heterooyoliaohe group with 1- or 2 nitrogen, oxygen and / or sulfur heteroatoates or the two R ¹ and R ² alkyl groups together with the coal 1 09885/1927 '^; atom to which they are bound, an oarbooyolisohea Form a system with 3-7 carbon atoms, 3. The method according to claim 1, characterized in that that compounds are used as starting materials in which R * Alkyl and R mean aryl, 4 ·. Method according to claim 1, characterized in that compounds are used as starting material in which R ο · Ifethyl, and R denotes phenyl. 5 ', process according to ftfethode a) of claim 1, characterized in that the reaction medium used is alcohol or Ben- a zol used. 6. The method according to method a) of claim 1, daduroh * characterized in that the secondary3 amine dialkylamines, Piperazine, Indpl, piperidine or their derivatives are used. -7. Method according to method a) of claim!, Characterized in that that the secondary amine used is morpholine. 8. The method according to method b) of claim 1, characterized daduroh, that one uses compounds of the formula IV., wherein A is a dialkylaraino-piperazinyl, indolyl, morpholinyl, or piperidyl group. ™ 9. The method according to claim 8, characterized in that as compounds of the formula IV. Morpholinyl - ^ - methyl-ethyl- -ether used. 10. The method according to any one of claims 1-6 ", characterized in that the compounds of formula I are converted into their halohydrates, sulphates, phosphates, borates, acetates, formates or citrates. ) 109885/1927