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DE1008297B - Process for the preparation of substituted succinimides - Google Patents

Process for the preparation of substituted succinimides

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Publication number
DE1008297B
DE1008297B DEP9150A DEP0009150A DE1008297B DE 1008297 B DE1008297 B DE 1008297B DE P9150 A DEP9150 A DE P9150A DE P0009150 A DEP0009150 A DE P0009150A DE 1008297 B DE1008297 B DE 1008297B
Authority
DE
Germany
Prior art keywords
chlorophenyl
ammonia
methylamine
preparation
methylsuccinic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
DEP9150A
Other languages
German (de)
Inventor
Loren Marlin Long
Charles Alexis Miller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Parke Davis and Co LLC
Original Assignee
Parke Davis and Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Parke Davis and Co LLC filed Critical Parke Davis and Co LLC
Priority to DEP9150A priority Critical patent/DE1008297B/en
Publication of DE1008297B publication Critical patent/DE1008297B/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

DEUTSCHESGERMAN

Die Erfindung bezieht sich auf ein Verfahren zur Herstellung von α- [o-Chlorphenyl] -a-methylsuccinimiden der allgemeinen FormelThe invention relates to a process for the preparation of α- [o-chlorophenyl] -a-methylsuccinimides the general formula

Verfahren zur Herstellung
von substituierten SuccinimidenMethod of manufacture
of substituted succinimides

H2CH 2 C

O = CO = C

CH3 CH 3

- C <■ - C <■

C = OC = O

ClCl

N RN R.

Anmelder:Applicant:

Parke, Davis & Company,
Detroit, Mich. (V. St. A.)Parke, Davis & Company,
Detroit, me. (V. St. A.)

Vertreter: Dr.-Ing. F. Wuesthoff, Dipl.-Ing. G. PulsRepresentative: Dr.-Ing. F. Wuesthoff, Dipl.-Ing. G. Pulse

und Dipl.-Chem. Dr. rer. nat. Frhr. E. v. Pechmann,and Dipl.-Chem. Dr. rer. nat. Mr. E. v. Bad luck man,

Patentanwälte, München 9, Sctrweigerstr. 2Patent Attorneys, Munich 9, Sctrweigerstr. 2

in der R ein Wasserstoffatom oder einen Methylrest bedeutet.in which R denotes a hydrogen atom or a methyl radical.

Es ist bereits bekannt, substituierte Succinimide durch Umsetzung von substituierten Bernsteinsäuren oder ihren Anhydriden mit Ammoniak und Erhitzen der erhaltenen Zwischenprodukte herzustellen.It is already known to replace substituted succinimides by reacting substituted succinic acids or to prepare their anhydrides with ammonia and heating the intermediate products obtained.

Gemäß der Erfindung wird nun α-[o-Chlorphenyl ]-a-methylbernsteinsäure oder or [o-Chlorphenyl]-a-methylbernsteinsäureanhydrid in an sich bekannter Weise mit Ammoniak oder Methylamin umgesetzt und das erhaltene Zwischenprodukt auf 100 bis 350° erhitzt.According to the invention there is now α- [o-chlorophenyl] -a-methylsuccinic acid or or [o-chlorophenyl] -a-methylsuccinic anhydride reacted in a manner known per se with ammonia or methylamine and the intermediate product obtained is heated to 100 to 350 °.

Bei der Durchführung der ersten Stufe des Verfahrens ist es vorteilhaft, ein inertes Lösungsmittel, wie Wasser, niedere aliphatische Alkohole oder deren Gemische, Äther, Benzol oder Toluol, zu verwenden, um die Reaktion der a-(oChlorphenyl)-cc-methylbern- 3D steinsäure oder ihres Anhydrids mit dem Ammoniak oder Methylamin zu erleichtern. Es werden vorzugsweise mehrere Mol Ammoniak oder Methylamin für 1 Mol α-[o-Chlorphenyl]-a-methylbernsteinsäure oder a- [o-Chlorphenyl] - α - methylbernsteinsäureanhydrid verwendet. Wird α-[o-Chlorphenyl]-α-methylbernsteinsäureanhydrid mit 1 Mol Ammoniak oder Methylamin umgesetzt, so ist das Zwischenprodukt das Halbamid, während bei der Verwendung von 2 oder mehr Mol Ammoniak oder Methylamin als Zwischenprodukt das Ammonium- bzw. Methylaminsalz des Halbamides der α- [o-Chlorphenyl] -a-methylbernsteinsäure gebildet wird. Bei Verwendung von a- [o-Chorphenyl] -a-methylbernsteinsäure als Ausgangsmaterial entsteht als Zwischenprodukt entweder das Mono- oder Diamonium- bzw. das entsprechende Methylaminsalz der α-[o-Chorphenyl]-a-methylbernsteinsäure. Wie oben angegeben, werden diese Zwischenprodukte in die Succinimide übergeführt, Beanspruchte Priorität:
V. St. v. Amerika vom 26. Februar 1952When carrying out the first stage of the process, it is advantageous to use an inert solvent, such as water, lower aliphatic alcohols or mixtures thereof, ethers, benzene or toluene, to prevent the reaction of the α- (o-chlorophenyl) -cc-methylben- 3 D stinic acid or its anhydride with ammonia or methylamine to facilitate. Several moles of ammonia or methylamine are preferably used for 1 mole of α- [o-chlorophenyl] -a-methylsuccinic acid or a- [o-chlorophenyl] -α-methylsuccinic anhydride. If α- [o-chlorophenyl] -α-methylsuccinic anhydride is reacted with 1 mole of ammonia or methylamine, the intermediate is the hemiamide, while when using 2 or more moles of ammonia or methylamine as an intermediate, the ammonium or methylamine salt of the hemiamide is the α- [o-Chlorophenyl] -a-methylsuccinic acid is formed. If a- [o-chlorophenyl] -a-methylsuccinic acid is used as the starting material, either the mono- or diamonium or the corresponding methylamine salt of α- [o-chlorophenyl] -a-methylsuccinic acid is formed as an intermediate product. As stated above, these intermediates are converted into the succinimides, priority claimed:
V. St. v. America February 26, 1952

Charles Alexis Miller, Detroit, Mich.,
und Loren Marlin Long, Grosse Pointe Woods,Charles Alexis Miller, Detroit, Mich.,
and Loren Marlin Long, Grosse Pointe Woods,

Mich. (V. St. A.),
sind als Erfinder genannt wordenMe. (V. St. A.),
have been named as inventors

indem man sie auf eine Temperatur zwischen 100 und 350° erhitzt. Die bevorzugte Temperatur liegt bei 190 bis 210°, bei der die Reaktion in etwa einer Stunde beendet ist.by heating them to a temperature between 100 and 350 °. The preferred temperature is 190 to 210 °, at which the reaction is complete in about an hour.

Die verfahrungsgemäß hergestellten substituierten Succinimide werden als Anticonvulsiva, insbesondere bei der Behandlung der Epilepsie in der petit-mal-Form, verwendet.The substituted succinimides prepared according to the method are used as anticonvulsants, in particular in the treatment of epilepsy in the petit mal form, used.

Es ist bereits bekannt, a-Methyl-a-phenylsuccinimid bzw. N-Methyl-a-methyl-a-phenylsuccinimid für die Behandlung der Epilepsie zu verwenden. Vergleicht man diese bekannten Verbindungen mit den verfahrungsgemäß hergestellten Succinimiden, so ergibt sich, wie aus der folgenden Tabelle hervorgeht, daß die bekannten Verbindungen starke toxische Nebenerscheinungen zeigen, die bei den α-[o-Chlorphenyl]-a-methylsuccinimiden nicht auftreten.It is already known a-methyl-a-phenylsuccinimide and N-methyl-a-methyl-a-phenylsuccinimide for the Use treatment of epilepsy. If one compares these known connections with those according to the method produced succinimides, it follows, as can be seen from the following table, that the known compounds show strong toxic side effects in the case of the α- [o-chlorophenyl] -a-methylsuccinimides do not occur.

709 509/400709 509/400

Substituierte SuccinimideSubstituted succinimides Orale Dosis
(mg/kg)Oral dose
(mg / kg) Anzahl der
verwendeten Ratten/
Anzahl der
gegen Krämpfe
geschützten Rattennumber of
rats used /
number of
against cramps
protected rats Toxische SymptomeToxic symptoms a-fo-Chlorphenylj-crmethylsuccinimid ....
a-Methyl-ct-pher.ylsuccinimid (bekannt) ....
N-Methyl-a- f o-chlorphenyl ] -a-methyl-
succinimid a-fo-chlorophenylj-crmethylsuccinimide ....
a-methyl-ct-pher.ylsuccinimid (known) ....
N-methyl-a- f o-chlorophenyl] -a-methyl-
succinimide 500
250
500
250
500
250
500
250500
250
500
250
500
250
500
250 5/55/5
5/55/5
5/55/5
5/55/5
5/55/5
5/55/5
5/55/5
5/55/5 keine
keine
Gleichgewichtsstörungen
keine
keine
Gleichgewichtsstörungen
Verlust des Greif reflexesno
no
Balance disorders
no
no
Balance disorders
Loss of the grasping reflex N-Methyl-a-methyl-ct-phenylsuccinimid ....
(bekannt)N-methyl-a-methyl-ct-phenylsuccinimide ....
(known)

Die Versuche wurden an Ratten nach dem Verfahren der Bestimmung der Anti-Metrazol-Wirksam- ao keit durchgeführt, wie es in Archives of Neurology and Psychiatry, Bd. 66 (1951), S. 329 bis 377, beschrieben ist. Hiernach wird diejenige Heilmittelmenge ermittelt, die bei den Ratten noch einen Schutz gegen durch Metrazol hervorgerufene Krämpfe gibt, wenn den Ratten eine Standardmenge Metrazol von 93 mg/kg verabreicht wird.The experiments were carried out on rats according to the method of determining the anti-metrazol efficacy ao as described in Archives of Neurology and Psychiatry, Vol. 66 (1951), pp. 329 to 377 is. The amount of remedy that still provides protection in the rats is then determined against convulsions caused by metrazol when the rats are given a standard dose of metrazol of 93 mg / kg is administered.

Das erfindungsgemäße Verfahren wird durch die folgenden Beispiele erläutert.The process according to the invention is illustrated by the following examples.

Beispiel 1example 1

14 g α - [ο - Chlorphenyl] - α - methylbernsteinsäure werden allmählich in 20 ecm konzentriertes Ammoniak gegeben. Wasser und überschüssiges Ammoniak werden durch Destillation entfernt. Anschließend wird die Temperatur des Rückstandes auf 200° erhöht und hier gehalten, bis kein Ammoniak mehr entwickelt wird. Der Rückstand wird in der Mindestmenge absolutem Alkohol gelöst, und die Lösung wird mit Aktivkohle entfärbt und filtriert. Aus dem gekühlten Filtrat wird das ct-[o-Chlorphenyl]-a-methylsuccinimid abgetrennt und getrocknet; F. 152 bis 155°; Ausbeute 79%.14 g of α - [ο - chlorophenyl] - α - methylsuccinic acid are gradually transformed into 20 ecm of concentrated ammonia given. Water and excess ammonia are removed by distillation. Afterward the temperature of the residue is increased to 200 ° and held here until no more ammonia is being developed. The residue is dissolved in the minimum amount of absolute alcohol, and the solution is decolorized with activated charcoal and filtered. The ct- [o-chlorophenyl] -a-methylsuccinimide is obtained from the cooled filtrate separated and dried; 152-155 °; Yield 79%.

Beispiel 2Example 2

9 g a-[o-Chlorphenyl]-a-methylbernsteinsäure werden allmählich in 15 ecm Wasser mit 40 Gewichtsprozent Methylamin gegeben. Wasser und der Methylaminüberschuß werden durch Destillation entfernt. Die Temperatur des Rückstandes wird auf 200° erhöht und hier gehalten, bis kein Methylamin mehr entwickelt wird. Der Rückstand wird aus absolutem Alkohol umkristallisiert unter Gewinnung des N-Methyl-a- [o-chlorphenyl]-a-methylsuccinimides; F. 120 bis 122°; Ausbeute 74%.9 g of a- [o-chlorophenyl] -a-methylsuccinic acid gradually added to 15 ecm of water containing 40 percent by weight of methylamine. Water and the excess methylamine are removed by distillation. The temperature of the residue is increased to 200 ° and held here until no more methylamine is evolved. The residue becomes absolute Recrystallized alcohol to give N-methyl-a- [o-chlorophenyl] -a-methylsuccinimide; F. 120 up to 122 °; Yield 74%.

Beispiel 3Example 3

10 g a - [ο- Chlorphenyl] -a-methylbernsteinsäureanhydrid werden allmählich in 10 ecm konzentriertes Ammoniak gegeben. Wasser und überschüssiges Ammoniak werden durch Destillation entfernt. Der10 g of a - [ο-chlorophenyl] -a-methylsuccinic anhydride are gradually added to 10 ecm of concentrated ammonia. Water and excess Ammonia are removed by distillation. Of the

45 Rückstand wird auf 210° erhitzt, bis kein Ammoniak mehr entwickelt wird, nach dem Abkühlen in absolutem Äthanol gelöst und mit Aktivkohle behandelt. In dem Filtrat fällt das a-[o-Chlorphenyl]-a-methylsuccinimid aus; F. 153 bis 155°; Ausbeute 82%.45 residue is heated to 210 ° until no more ammonia is evolved, after cooling in absolute Dissolved ethanol and treated with activated charcoal. The a- [o-chlorophenyl] -a-methylsuccinimide falls in the filtrate the end; 153-155 °; Yield 82%.

Claims (2)

Patentansprüche:Patent claims: 1. Verfahren zur Herstellung von substituierten Succinimiden durch Umsetzung von substituierten Bernsteinsäuren oder substituierten Bernsteinsäureanhydriden mit Ammoniak oder Methylamin und Erhitzen der erhaltenen Zwischenprodukte auf 100 bis 350°, dadurch gekennzeichnet, daß α- [ο-Chlorphenyl] -α-methylbernsteinsäure bzw. α- [o-Chlorphenyl] -α-methylbernsteinsäureanhydrid zu α- [o-Chlorphenyl] -a-methylsuccinimiden der allgemeinen Formel1. A process for the preparation of substituted succinimides by reacting substituted succinic acids or substituted succinic anhydrides with ammonia or methylamine and heating the intermediate products obtained to 100 to 350 °, characterized in that α- [ο-chlorophenyl] -α-methylsuccinic acid or α- [o-Chlorophenyl] -α-methylsuccinic anhydride to α- [o-chlorophenyl] -a -methylsuccinimides of the general formula CHR CH R H2C-O = CH 2 CO = C ClCl in der R ein Wasserstoffatom oder einen Methylrest bedeutet, umgesetzt wird.in which R is a hydrogen atom or a methyl radical, is reacted. 2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß die Zwischenprodukte auf 190 bis 210° erhitzt werden.2. The method according to claim 1, characterized in that the intermediate products to 190 to 210 ° can be heated. In Betracht gezogene Druckschriften:
Deutsche Patentschrift Nr. 389 948;Considered publications:
German Patent No. 389,948; Hoppe-Segler's Zeitschrift für Physiologische Chemie, Bd. 226 (1934), S. 98 und 103;Hoppe-Segler's Journal for Physiological Chemistry, Vol. 226 (1934), pp. 98 and 103; Archives of Neurology and Psychiatry, Bd. 66 (1951), S. 156 bis 162;Archives of Neurology and Psychiatry, 66: 156-162 (1951); Journal of the American Chemical Society, Bd. 73 (1951), S. 4895 bis 4898.Journal of the American Chemical Society, 73, 4895-4898 (1951). © 703 509/400 5.© 703 509/400 5.
DEP9150A 1953-02-05 1953-02-05 Process for the preparation of substituted succinimides Pending DE1008297B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DEP9150A DE1008297B (en) 1953-02-05 1953-02-05 Process for the preparation of substituted succinimides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DEP9150A DE1008297B (en) 1953-02-05 1953-02-05 Process for the preparation of substituted succinimides

Publications (1)

Publication Number Publication Date
DE1008297B true DE1008297B (en) 1957-05-16

Family

ID=588694

Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Status (1)

Country Link
DE (1) DE1008297B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE389948C (en) * 1922-08-01 1924-02-09 Hoechst Ag Process for the preparation of CíñC-substituted succinimides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE389948C (en) * 1922-08-01 1924-02-09 Hoechst Ag Process for the preparation of CíñC-substituted succinimides

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