EP0362350A1 - Process for producing 5-member nitrogen-containing hetero-aromatic compounds - Google Patents

Process for producing 5-member nitrogen-containing hetero-aromatic compounds

Info

Publication number
EP0362350A1
EP0362350A1 EP89904057A EP89904057A EP0362350A1 EP 0362350 A1 EP0362350 A1 EP 0362350A1 EP 89904057 A EP89904057 A EP 89904057A EP 89904057 A EP89904057 A EP 89904057A EP 0362350 A1 EP0362350 A1 EP 0362350A1
Authority
EP
European Patent Office
Prior art keywords
formula
atoms
carboxylic acid
compounds
methyl
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
EP89904057A
Other languages
German (de)
French (fr)
Inventor
Richard Kirchlechner
Michael Casutt
Arno Basedow
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.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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 Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP0362350A1 publication Critical patent/EP0362350A1/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates to a process for the preparation of compounds of formula I.
  • X 1 and X2 each independently of one another • CO-OR2, CO-NR3R4 or CN,
  • R 1 and R2 are each independently hydrogen
  • R 3 and R4 are each independently of one another alkyl with 1-7
  • R and X have the meaning given in the synthesis of imidazole alkaloids such as e.g. Isomacrorin or pilocarpine used.
  • the invention therefore relates to a process for the preparation of compounds of the formula I.
  • X 1 and X are each independently CO-OR2, CO-NR3R4 or CN, and
  • R 1 and R2 are each independently hydrogen
  • R and R each independently of one another alkyl 1 with 1-7
  • R 3 and R4 have the meaning given
  • the invention relates in particular to a process for the preparation of the compounds of the formula Ia, in which A is NR.
  • the invention furthermore relates to the use of the compounds of the formula I, in particular of the formula Ia, prepared by the process according to the invention, for the preparation of active pharmaceutical ingredients, in particular pilocarpine.
  • R 1 and R 2 are each independently of one another hydrogen, alkyl having 1-7 C atoms or carbocyclic radicals.
  • R 1 and / or R2 represent an alkyl radical, this can be straight-chain or branched. This means methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, i-propyl, 1- (or 2-) methyl propyl, tert.
  • R 1 and / or R2 represent a carbocyclic radical, this can be aromatic, cycloaliphatic or araliphatic. This means preferably phenyl, benzyl,
  • Cyclohexyl 1-indanyl, tetrahydronaphthyl (e.g. 1,2,3,4-tetrahydro-1-naphthyl), benzocycloheptyl (e.g. 5-benzocycloheptyl), 9,10-dihydro-9-anthracenyl, 9H-fluorene-9 -yl,
  • the carbocyclic radicals mentioned above can each be unsubstituted or substituted with 1 to 6 substituents selected from the group consisting of alkyl, alkoxy with 1-5 C atoms and halogen.
  • the group R 3R4N- preferably denotes an N, N-diethyl, N, N-diethyl, N, N-dipropyl, N, N-diisopropyl,
  • N N-dibutyl, N ⁇ N-diisobutyl, N, N-di-sec-butyl, N, N
  • Di- (o-, m- or p-tolyl) amino residue or a morpholino, piperidino or N-methylanilino residue Di- (o-, m- or p-tolyl) amino residue or a morpholino, piperidino or N-methylanilino residue.
  • anion Y is likewise not critical for the course of the reaction; it preferably means Cl ⁇ or Br ⁇ .
  • NR glycine or aminoacetonitrile derivatives
  • Ilb: A CH-X 2: succinic acid derivatives
  • can by known methods as described in the literature for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart ) are, namely according to reaction conditions, as they are known and suitable for the reactions mentioned, are prepared. Use can also be made of variants which are known per se and are not mentioned here in detail.
  • the starting materials of the formula III are also known and can be prepared from cyanuric chloride and N, N-dialkylformamides.
  • the reaction of the methylene compound of formula II with the salt of formula III is preferably carried out in an inert solvent in the presence of a base.
  • Suitable bases are, depending on the CH acidity of the methylene compound used, for example alkali or alkaline earth metal hydroxides such as lithium, calcium, barium, sodium or potassium hydroxide, alkali metal carbonates such as sodium or potassium carbonate, alcoholates such as sodium methylate, sodium ethylate, lithium ethylate or potassium tert-butoxide, alkali metal amides such as potassium or sodium amide, or orga ⁇ African bases such as triethylamine, pyridine, 4-N, N-dimethylaminopyridine, lutidine, piperidine, morpholine, piperazine, collidine or quinoline, lithium diisopropylamide or lithium tetraethylpiperidide.
  • Suitable inert solvents are preferably ethers such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, tert-butyl methyl ether or dioxane and amides such as dimethylformamide, N, N-dimethylpropylene urea, dirthylacetamide or N-methylpyrrolidone, furthermore sulfoxides such as dimethyl sulfoxide or sulfones such as sulfolane Hydrocarbons such as pentane, hexane, cyclohexane, benzene or toluene.
  • ethers such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, tert-butyl methyl ether or dioxane
  • amides such as dimethylformamide, N, N-dimethylpropylene urea, dirthylacetamide or N-methylpyrrolidone
  • reaction temperatures are expediently between -78 ° C. and +150 ° C., preferably between +20 ° C. and +100 ° C., and the reaction times are between 1 and 48 hours, depending on the reactivity of the methyl compound used.
  • both the carboxylic acid esters of the formula I in which X 1 is CO-OR2 can be used as the carboxamides of the formula I in which X .1 is CO-NR 3R4 also arise.
  • the ratio of the resulting products can easily be controlled by a suitable choice of the reaction conditions.
  • non-enolizable carboxylic acid esters which are suitable for trapping the amines formed in the reaction from the salt of formula III.
  • non-enolizable carboxylic acid esters are the methyl or ethyl esters of the corresponding carboxylic acid, such as, for example, benzoic acid, phthalic or terephthalic acid, perfluoroalkyl acids, such as trifluoroacetic acid, or the aliphatic carboxylic acid, which has no hydrogen atoms ⁇ to the carboxyl group, such as eg pivalic acid or oxalic acid.
  • the carboxamides of the formula I in which X 1 or X1 and X2 is CO-NR3R4 can also be prepared in a targeted manner by the reaction without the addition of such
  • Y " ⁇ come inorganic acid residues such as F, Cl, Br, J, J_, HSO., H P0. Or CIO., But also organic acid residues such as carboxylates, especially acetate or trifluoroacetate, or sulfonates, especially p-toluenesulfonate, Trifluoromethanesulfonate or methanesulfonate, with chlorides being particularly preferred.
  • the 5-membered, nitrogen-containing heterocycles which can be prepared by the process according to the invention are also valuable starting materials for the production of dyes, crop protection agents and other pharmaceuticals or are themselves suitable, such as, for example, in EP-OS 0207563, as a means of influencing plant growth.
  • the process according to the invention thus allows the preparation of compounds of the formula I, in particular of the formula Ia, in a simple manner in high yields from easily accessible, inexpensive starting materials in a single synthesis step to be carried out in a one-pot process and thus represents a significant step forward in the process Field of synthesis of compounds of formula I, in particular in pilocarpine synthesis.
  • a suspension of 189.07 g of sodium methylate in 2000 ml of dioxane is initially introduced under nitrogen at room temperature, 181.45 g of sarcosine methyl ester hydrochloride and 261.84 g of 3-dimethylamino-2-azaprop-2- en-l-ylidene-dimethylammonium chloride and the reaction mixture is stirred at 60 ° C. for 24 hours.
  • a suspension of 54.03 g of sodium methylate in 600 ml of dioxane is introduced under nitrogen at room temperature, and 41.87 g of sarcosine methyl ester hydrochloride, 65.46 g of 3-dimethylamino-2-azaprop-2-ene 1- are carried in succession.
  • ylidene-dimethylammonium chloride and 47.24 g of dimethyl oxalate and the reaction mixture is stirred at 65 ° C. for 12 hours. It is then suctioned off through diatomaceous earth, washed with dioxane and concentrated under reduced pressure.
  • a suspension of 162 g of sodium methylate in 2000 ml of dioxane is initially introduced under nitrogen at room temperature, 139.6 g of sarcosine methyl ester hydrochloride and 212.7 g of 3-dimethylamino-2-azaprop-2-ene are carried in succession with stirring. l-ylidene-dimethylammonium chloride and the reaction mixture is stirred at 90 ° C. for 24 hours.
  • a mixture of 4.5 is added at -78 ° C. to a mixture of lithium diisopropylamide (made from 3.0 g of diisopropylamine and 19 ml of a 15% solution of n-butyllithium in hexane) and 15 ml of tetrahydrofuran, which is kept under nitrogen g of succinic acid dibenzyl ester and 10 ml of tetrahydrofuran. After warming up to 0 ° C., 3.1 g of 3-dimethylamino-2-azaprop-2-en-1-ylidene-dimethylammonium chloride are added and the mixture is stirred for 24 hours at boiling temperature.
  • Potassium hydride (4.15 g, 35% oil suspension) is washed twice with 15 ml of hexane and suspended in 150 ml of diethylene glycol.
  • 11.6 g of diethyl (cyan (1- (tert-butoxycarbonyl) propyl) methyl) phosphonate (prepared according to Ref.) are added to this mixture at 0 ° C.
  • a mixture of 4.0 g of 1-methyl-1H-imidazole-5-carboxaldehyde (prepared from 1-methyl-1H-imidazolecarboxylic acid methyl ester J according to Ref. 2) and 20 ml Add diethylene glycol and stir for 12 hours at room temperature.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Hydrogenated Pyridines (AREA)
  • Luminescent Compositions (AREA)

Abstract

PCT No. PCT/EP89/00335 Sec. 371 Date Dec. 6, 1989 Sec. 102(e) Date Dec. 6, 1989 PCT Filed Mar. 25, 1989 PCT Pub. No. WO89/09768 PCT Pub. Date Oct. 19, 1989.Compounds of the formula I <IMAGE> I in which A and X1 have the meaning given in patent claim 1 can be prepared in a simple manner, in a one-pot process and in high yields.

Description

Verfahren zur Herstellung von 5-gliedrigen, stickstoff¬ haltigen HeteroaromatenProcess for the preparation of 5-membered, nitrogen-containing heteroaromatics
Die Erfindung betrifft ein Verfahren zur Herstellung von Verbindungen Formel IThe invention relates to a process for the preparation of compounds of formula I.
worinwherein
A NR1 oder CH-X ,A NR 1 or CH-X,
X 1 und X2 jeweils unabhängi•g voneinander CO-OR2, CO-NR3R4 oder CN,X 1 and X2 each independently of one another • CO-OR2, CO-NR3R4 or CN,
R 1 und R2 jeweils unabhängig voneinander Wasserstoff,R 1 and R2 are each independently hydrogen,
Alkyl mit 1-8 C-Atomen, oder einen carbocyc- lischen Rest undAlkyl with 1-8 carbon atoms, or a carbocyclic radical and
R 3 und R4 jewei.ls unabhängi•g voneinander Alkyl mit 1- -7-R 3 and R4 are each independently of one another alkyl with 1-7
C-Atomen, Aryl mit 6-8 C-Atomen oder Aralkyl mit 7-13 C-Atomen oder auch jeweils zusammen mit dem benachbarten Stickstoffatom einen heterocyclischen Rest mit 2-6 C-Atomen, wobei auch eine CH2~Gruppe durch 0, S oder^ NH er¬ setzt sein kann, bedeuten. Der Erfindung lag die Aufgabe zugrunde, ein neues Verfahren für die Herstellung der Verbindungen der Formel I bereit¬ zustellen, das diese Verbindungen mit Hilfe einfacher Reak¬ tionen in hoher Ausbeute zugänglich macht.C-atoms, aryl with 6-8 C-atoms or aralkyl with 7-13 C-atoms or also together with the neighboring nitrogen atom a heterocyclic radical with 2-6 C-atoms, whereby also a CH 2 ~ group by 0, S or ^ NH can be replaced. The invention was based on the object of providing a new process for the preparation of the compounds of the formula I which makes these compounds accessible in high yield with the aid of simple reactions.
Verbindungen der Formel I sind wertvolle Synthesezwischen- produkte; insbesondere werden die Verbindungen der Formel la,Compounds of the formula I are valuable synthetic intermediates; in particular the compounds of the formula Ia,
| |
ΈΓΈΓ
worin R und X die angegebene Bedeutung besitzen, bei der Synthese von Imidazol-Alkaloiden wie z.B. Isomacrorin oder Pilocarpin eingesetzt.where R and X have the meaning given in the synthesis of imidazole alkaloids such as e.g. Isomacrorin or pilocarpine used.
la (X1 = COOR2) kann nach EP-OS 0207563 ausgehend von N- Alkylglycinester-Hydrochloriden in 4 Stufen hergestellt werden.la (X 1 = COOR 2 ) can be prepared in 4 stages according to EP-OS 0207563 starting from N-alkylglycine ester hydrochlorides.
Aus dem N-Methylacetammomalonsäurediethylester wird la (R 1 = CH.., X1 = COOR2) in einer 5stufιgen Synthese er- halten.La (R 1 = CH .., X1 = COOR2) is obtained in a 5-step synthesis from the diethyl N-methylacetammomalonate.
In einem weiteren 5stufigen Verfahren kann Diamino aleo- nitril mit Orthoameisensäuretriethylester zum I idazol- 4,5-dinitril umgesetzt werden, welches nach Alkylierung mit Dimethylsulfat, Hydrolyse und partieller Decarboxy- lierung durch Erhitzen in Acetanhydrid die Verbindung der Formel la (R1 = CHg, X1 = COOH) ergibt.In a further 5-step process, diamino aleonitrile can be reacted with triethyl orthoformate to give idazole-4,5-dinitrile, which, after alkylation with dimethyl sulfate, hydrolysis and partial decarboxylation by heating in acetic anhydride, gives the compound of the formula Ia (R 1 = CHg , X 1 = COOH) results.
Alle diese Verfahren sind jedoch durch eine hohe Zahl von Syntheseschritten und damit eine niedrige Gesamtausbeute gekennzeichne . Obwohl bekannt ist, daß man bei Umsetzung von 3-Dimethyl- amino-2-azaprop-2-en-l-yliden-dimethylammoniumchlorid (Gold's Reagenz) mit Hydrazinen 1,3,4-Triazole erhält, gibt es keinen Hinweis, daß sich dieses Reagenz auch zur Her- Stellung von anderen 5gliedrigen Heterocyclen verwenden läßt.However, all of these processes are characterized by a high number of synthesis steps and thus a low overall yield. Although it is known that when 3-dimethylamino-2-azaprop-2-en-1-ylidene-dimethylammonium chloride (Gold's reagent) is reacted with hydrazines, 1,3,4-triazoles are obtained, there is no indication that this reagent can also be used to prepare other 5-membered heterocycles.
Es wurde nun überraschend gefunden, daß Verbindungen der Formel I, insbesondere der Formel la, durch Umsetzung von Methylen-Verbindungen der Formel II oder deren Säureaddi- tionssalzen mit Aminomethylenformamidinium-Salzen der For¬ mel III in einem einzigen Syntheseschritt, im Eintopfver¬ fahren und in hohen Ausbeuten hergestellt werden können.It has now surprisingly been found that compounds of the formula I, in particular of the formula Ia, can be reacted by reacting methylene compounds of the formula II or their acid addition salts with aminomethyleneformamidinium salts of the formula III in a single synthesis step, and can be produced in high yields.
Gegenstand der Erfindung ist daher ein Verfahren zur Her¬ stellung von Verbindungen der Formel IThe invention therefore relates to a process for the preparation of compounds of the formula I.
worinwherein
A . , NR1 oder CH-X2, A. , NR 1 or CH-X 2 ,
X 1 und X jeweils unabhängig voneinander CO-OR2, CO-NR3R4 oder CN, undX 1 and X are each independently CO-OR2, CO-NR3R4 or CN, and
R 1 und R2 jeweils unabhängig voneinander Wasserstoff,R 1 and R2 are each independently hydrogen,
Alkyl mit 1-8 C-Atomen oder einen carbocyc- lischen Rest, undAlkyl with 1-8 carbon atoms or a carbocyclic radical, and
R und R jeweils unabhängig voneinander Alkyl1 mit 1-7R and R each independently of one another alkyl 1 with 1-7
C-Atomen, Aryl mit 6-8 C-Atomen oder Aralkyl mit 7-13 C-Atomen oder auch jeweils zusammen mit dem benachbarten Stickstoffatom einen heterocyclischen Rest mit 2-6 C-Atomen, wobei auch eine CH2-Gruppe durch O, S oder NH er¬ setzt sein kann,C atoms, aryl with 6-8 C atoms or aralkyl with 7-13 C atoms or also together with the neighboring nitrogen atom a heterocyclic radical with 2-6 C atoms, whereby a CH 2 group can also be replaced by O, S or NH,
bedeuten, dadurch gekennzeichnet, daß man eine Methylen- Verbindung der Formel IImean, characterized in that a methylene compound of the formula II
X^CH^-AH IIX ^ CH ^ -AH II
- oder eines ihrer Säureadditionssalze, worin X und A die angegebene Bedeutung besitzen, mit einem Salz der Formel III,- or one of its acid addition salts, in which X and A have the meaning given, with a salt of the formula III,
worinwherein
R 3 und R4 die angegebene Bedeutung besitzten, undR 3 and R4 have the meaning given, and
Yθ Clθ, Brθ, Jθ, j , CIO® oder BFj bedeutet,Y θ Cl θ , Br θ , J θ , j, CIO ® or BFj means
und einer Base umsetzt.and implement a base.
Gegenstand der Erfindung ist insbesondere ein Verfahren zur Herstellung der Verbindungen der Formel la, worin A NR bedeutet.The invention relates in particular to a process for the preparation of the compounds of the formula Ia, in which A is NR.
und die Verbindung der Formel Ha in Form eines Säure- additionssalzes mit einer Verbindung der Formel III umgesetzt wird. Gegenstand der Erfindung ist ferner die Verwendung der nach dem erfindungsgemäßen Verfahren hergestellten Ver¬ bindungen der Formel I, insbesondere der Formel la, zur Herstellung von Arzneimittelwirkstoffen, insbesondere von Pilocarpin.and the compound of the formula Ha is reacted in the form of an acid addition salt with a compound of the formula III. The invention furthermore relates to the use of the compounds of the formula I, in particular of the formula Ia, prepared by the process according to the invention, for the preparation of active pharmaceutical ingredients, in particular pilocarpine.
Das erfindungsgemäße Verfahren ergibt unabhängig von der Beschaffenheit der Gruppen A, X 1, X2, R1, R2, R3, R4 undThe method according to the invention results regardless of the nature of groups A, X 1, X2, R1, R2, R3, R4 and
X die entsprechenden Verbindungen der Formel I in durch¬ weg hohen Ausbeuten.X the corresponding compounds of formula I in consistently high yields.
Falls A NR1 und X1 COOR2 bedeutet, sind R1 und R2 jeweils unabhängig voneinander Wasserstoff, Alkyl mit 1-7-C-Atomen oder carbocyclische Reste.If A is NR 1 and X 1 is COOR 2 , R 1 and R 2 are each independently of one another hydrogen, alkyl having 1-7 C atoms or carbocyclic radicals.
Falls R 1 und/oder R2 einen Alkylrest bedeuten, so kann dieser geradkettig oder verzweigt sein. Dieser bedeutet somit Methyl, Ethyl, n-Propyl, n-Butyl, n-Pentyl, n-Hexyl, n-Heptyl, n-Octyl, i-Propyl, l-(bzw. 2-)Methylpropyl, tert.If R 1 and / or R2 represent an alkyl radical, this can be straight-chain or branched. This means methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, i-propyl, 1- (or 2-) methyl propyl, tert.
Butyl, l-(2- bzw. 3-)Methylbutyl, neo-Pentyl, l-(2-, 3- bzw. 4-)Methylpentyl, 1- (2-, 3-, 4- bzw. 5-)Methylhexyl oder 2-Ethylhexyl (i-Octyl). Vorzugsweise bedeutet er Methyl, Ethyl oder i-Propyl, insbesondere Methyl.Butyl, 1- (2- or 3-) methylbutyl, neo-pentyl, 1- (2-, 3- or 4-) methylpentyl, 1- (2-, 3-, 4- or 5-) methylhexyl or 2-ethylhexyl (i-octyl). It preferably means methyl, ethyl or i-propyl, in particular methyl.
Falls R 1 und/oder R2 einen carbocyclischen Rest bedeuten, so kann dieser aromatisch, cycloaliphatisch oder aralipha- tisch sein. Dieser bedeutet somit bevorzugt Phenyl, Benzyl,If R 1 and / or R2 represent a carbocyclic radical, this can be aromatic, cycloaliphatic or araliphatic. This means preferably phenyl, benzyl,
Cyclohexyl, 1-Indanyl, Tetrahydronaphthyl (z.B. 1,2,3,4- Tetrahydro-1-naphthyl) , Benzocycloheptyl, (z.B. 5-Benzo- cycloheptyl), 9,10-Dihydro-9-anthracenyl, 9H-Fluoren-9-yl,Cyclohexyl, 1-indanyl, tetrahydronaphthyl (e.g. 1,2,3,4-tetrahydro-1-naphthyl), benzocycloheptyl (e.g. 5-benzocycloheptyl), 9,10-dihydro-9-anthracenyl, 9H-fluorene-9 -yl,
5-Dibenzo[a,d]cycloheptyl oder Dihydronaphthyl (z.B. 1,2-5-dibenzo [a, d] cycloheptyl or dihydronaphthyl (e.g. 1,2-
Dihydro-1-naphthyl) . Die vorstehend genannten carbocyclischen Reste können jeweils unsubstituiert oder mit 1 bis 6 Substituenten, ausgewählt aus der Gruppe Alkyl, Alkoxy mit 1-5 C-Atomen und Halogen, substituiert sein.Dihydro-1-naphthyl). The carbocyclic radicals mentioned above can each be unsubstituted or substituted with 1 to 6 substituents selected from the group consisting of alkyl, alkoxy with 1-5 C atoms and halogen.
Die Gruppe R 3R4N- bedeutet vorzugsweise einen N,N-Di- ethyl-, N,N-Diethyl-, N,N-Dipropyl-, N,N-Diisopropyl-,The group R 3R4N- preferably denotes an N, N-diethyl, N, N-diethyl, N, N-dipropyl, N, N-diisopropyl,
N N-Dibutyl-, NΛN-Diisobutyl-, N,N-Di-sek-butyl-, N,N-N N-dibutyl, N Λ N-diisobutyl, N, N-di-sec-butyl, N, N
Dicyclohexyl- r N,N-Dibenzyl-, N,N-Diphenyl- oder N,N-Dicyclohexyl- r N, N-dibenzyl-, N, N-diphenyl- or N, N-
Di-(o-, m- oder p-Tolyl)-amino-Rest bzw. einen Morpho- lino-, Piperidino- oder N-Methylanilinorest.Di- (o-, m- or p-tolyl) amino residue or a morpholino, piperidino or N-methylanilino residue.
Für den Reaktionsablauf ebenfalls unkritisch ist die Be¬ deutung des Anions Y ; es bedeutet bevorzugt Clθ oder Brθ.The importance of the anion Y is likewise not critical for the course of the reaction; it preferably means Cl θ or Br θ .
Die AusgangsStoffe der Formel II sind bekannt (Ha: A =The starting materials of formula II are known (Ha: A =
NR : Glycin- bzw. Aminoacetonitril-Derivate; Ilb: A = CH-X 2: Bernsteinsäure-Derivate) oder können nach bekann¬ ten Methoden, wie sie in der Literatur beschrieben (z.B. in Standardwerken wie Houben-Weyl, Methoden der Organi¬ schen Chemie, Georg-Thieme-Verlag, Stuttgart) sind, und zwar nach Reaktionsbedingungen, wie sie für die genannten Umsetzungen bekannt und geeignet sind, hergestellt werden. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.NR: glycine or aminoacetonitrile derivatives; Ilb: A = CH-X 2: succinic acid derivatives) or can by known methods as described in the literature (for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart ) are, namely according to reaction conditions, as they are known and suitable for the reactions mentioned, are prepared. Use can also be made of variants which are known per se and are not mentioned here in detail.
Die Ausgangsstoffe der Formel III sind ebenfalls bekannt und können aus Cyanurchlorid und N,N-Dialkylformamiden hergestellt werden.The starting materials of the formula III are also known and can be prepared from cyanuric chloride and N, N-dialkylformamides.
Die Umsetzung der Methylen-Verbindung der Formel II mit dem Salz der Formel III erfolgt vorzugsweise in einem inerten Lösungsmittel in Anwesenheit einer Base. Als Basen eignen sich in Abhängigkeit von der C-H-Acidität der ein- gesetzten Methylen-Verbindung z.B. Alkali- bzw. Erdalkali- metallhydroxide wie Lithium-, Calcium-, Barium-, Natrium¬ oder Kaliumhydroxid, Alkalimetallcarbonate wie Natrium¬ oder Kaliumcarbonat, Alkoholate wie Natriummethylat, Na- triumethylat, Lithiumethylat oder Kalium-tert.-butylat, Alkalimetallamide wie Kalium- oder Natriumamid, oder orga¬ nische Basen wie Triethylamin, Pyridin, 4-N,N-Dimethyl- aminopyridin, Lutidin, Piperidin, Morpholin, Piperazin, Collidin oder Chinolin, Lithiumdiisopropylamid oder Li- thiumtetra ethylpiperidid.The reaction of the methylene compound of formula II with the salt of formula III is preferably carried out in an inert solvent in the presence of a base. Suitable bases are, depending on the CH acidity of the methylene compound used, for example alkali or alkaline earth metal hydroxides such as lithium, calcium, barium, sodium or potassium hydroxide, alkali metal carbonates such as sodium or potassium carbonate, alcoholates such as sodium methylate, sodium ethylate, lithium ethylate or potassium tert-butoxide, alkali metal amides such as potassium or sodium amide, or orga¬ African bases such as triethylamine, pyridine, 4-N, N-dimethylaminopyridine, lutidine, piperidine, morpholine, piperazine, collidine or quinoline, lithium diisopropylamide or lithium tetraethylpiperidide.
Zweckmäßig führt man die Reaktion in einem inerten Lö¬ sungsmittel durch. Als inerte Lösungsmittel eignen sich vorzugsweise Ether wie Diethylether, Ethylenglykoldimethyl- ether, Tetrahydrofuran, tert.-Butylmethylether oder Dioxan sowie Amide wie Dimethylformamid, N,N-Dimethylpropylenharn- stoff, Dirnethylacetamid oder N-Methylpyrrolidon, ferner Sulfoxide wie Dimethylsulfoxid oder Sulfone wie Sulfolan sowie Kohlenwasserstoffe wie Pentan, Hexan, Cyclohexan, Benzol oder Toluol. Die Reaktionstemperaturen liegen zweck¬ mäßig entsprechend der Reaktivität der eingesetzten Methy- len-Verbindung zwischen -78 °C und +150 °C, vorzugsweise zwischen +20 °C und +100 °C, die Reaktionszeiten zwischen 1 und 48 Stunden.The reaction is expediently carried out in an inert solvent. Suitable inert solvents are preferably ethers such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, tert-butyl methyl ether or dioxane and amides such as dimethylformamide, N, N-dimethylpropylene urea, dirthylacetamide or N-methylpyrrolidone, furthermore sulfoxides such as dimethyl sulfoxide or sulfones such as sulfolane Hydrocarbons such as pentane, hexane, cyclohexane, benzene or toluene. The reaction temperatures are expediently between -78 ° C. and +150 ° C., preferably between +20 ° C. and +100 ° C., and the reaction times are between 1 and 48 hours, depending on the reactivity of the methyl compound used.
Bei der Umsetzung der Verbindungen der Formel II, worin X 1 CO-OR2 bedeutet, mit dem Salz der Formel III können, bedingt durch die Reaktivität dieser Edukte, sowohl die Carbonsäureester der Formel I, worin X 1 CO-OR2 bede ;uutet, als auch die Carbonsäureamide der Formel I, worin X .1 CO-NR 3R4 bedeutet, entstehen. Das Verhältnis der ent¬ stehenden Produkte läßt sich durch geeignete Wahl der Reaktionsbedingungen leicht steuern.When reacting the compounds of the formula II in which X 1 is CO-OR2 with the salt of the formula III, owing to the reactivity of these starting materials, both the carboxylic acid esters of the formula I in which X 1 is CO-OR2 can be used as the carboxamides of the formula I in which X .1 is CO-NR 3R4 also arise. The ratio of the resulting products can easily be controlled by a suitable choice of the reaction conditions.
Zur vollständigen Unterdrückung der Bildung von Carbon- säureamiden der Formel I ist von Vorteil, die Reaktion in Gegenwart von nicht enolisierbaren Carbonsäurestern durch- zuführen, die geeignet sind, die bei der Reaktion aus dem Salz der Formel III gebildeten Amine abzufangen. Besonders geeignete nicht enolisierbare Carbonsäureester sind die Methyl- oder Ethylester der entsprechenden Carbonsäure wie z.B. Benzoesäure-, Phtalsäure- oder Terephtalsäure, der Perfluoralkylsäuren, wie z.B. Trifluoressigsäure, oder der aliphatischen Carbonsäure, welche keine zur Car- boxylgruppe α-ständige Wasserstof atome aufweist, wie z.B. Pivalylsäure oder Oxalsäure.To completely suppress the formation of carboxylic acid amides of the formula I, it is advantageous to carry out the reaction in the presence of non-enolizable carboxylic acid esters. supply, which are suitable for trapping the amines formed in the reaction from the salt of formula III. Particularly suitable non-enolizable carboxylic acid esters are the methyl or ethyl esters of the corresponding carboxylic acid, such as, for example, benzoic acid, phthalic or terephthalic acid, perfluoroalkyl acids, such as trifluoroacetic acid, or the aliphatic carboxylic acid, which has no hydrogen atoms α to the carboxyl group, such as eg pivalic acid or oxalic acid.
Andererseits lassen sich die Carbonsäureamide der Formel I, worin X 1 bzw. X1 und X2 CO-NR3R4 bedeutet, auch gezielt herstellen, indem man die Reaktion ohne Zusatz solcherOn the other hand, the carboxamides of the formula I in which X 1 or X1 and X2 is CO-NR3R4 can also be prepared in a targeted manner by the reaction without the addition of such
Carbonsäureestern bei erhöhter Temperatur und längererCarboxylic acid esters at elevated temperature and longer
Reaktionszeit durchführt.Response time.
Bevorzugt werden Verbindungen der Formel Ha (A bedeutet NR ) in Form ihrer Säure-Additionssalze Ila'Compounds of the formula Ha (A denotes NR) in the form of their acid addition salts Ila 'are preferred
X1-CH2-NHR1 - HY1 Ha'X 1 -CH 2 -NHR 1 - HY 1 Ha '
eingesetzt.used.
Als Y"^ kommen anorganische Säurereste wie F, Cl, Br, J, J_, HSO., H P0. oder CIO., aber auch organische Säurereste wie Carboxylate, vor allem Acetat oder Trifluoracetat, oder Sulfonate, vor allem p-Toluolsulfonat, Trifluormethansul- fonat oder Methansulfonat, in Betracht. Insbesondere bevor¬ zugt sind die Chloride.As Y "^ come inorganic acid residues such as F, Cl, Br, J, J_, HSO., H P0. Or CIO., But also organic acid residues such as carboxylates, especially acetate or trifluoroacetate, or sulfonates, especially p-toluenesulfonate, Trifluoromethanesulfonate or methanesulfonate, with chlorides being particularly preferred.
In einer besonders bevorzugten Ausführungsform des er¬ findungsgemäßen Verfahrens wird ein Hydrochlorid der For¬ mel Ila (Y = Cl) zusammen mit einem Aminomethylenforma- midiniumchlorid (Y = Cl) der Formel III bei -10 °C bis +30 °C zu einem Gemisch eines Alkalimetallalkoholates, vorzugsweise Natriummethylat oder Natriu ethylat, und eines inerten Lösungsmittels, vorzugsweise eines Kohlen¬ wasserstoffes wie Cyclohexan oder Toluol oder eines Ethers, wie z.B. Dioxan oder Tetrahydrofuran, gegeben und anschließend 1 bis 30 Stunden bei Temperaturen zwi¬ schen 0° und 130 °C gerührt.In a particularly preferred embodiment of the process according to the invention, a hydrochloride of the formula Ila (Y = Cl) together with an aminomethyleneformaminium chloride (Y = Cl) of the formula III at -10 ° C. to +30 ° C. becomes a mixture an alkali metal alcoholate, preferably sodium methylate or sodium ethylate, and an inert solvent, preferably a hydrocarbon such as cyclohexane or toluene or an ether, such as dioxane or tetrahydrofuran, and then stirred for 1 to 30 hours at temperatures between 0 ° and 130 ° C.
Verbindungen der Formel I, insbesondere der Formel la, sind bekannt und können nach bekannten Methoden, wie z.B. in Helv. Chim. Acta 5J5, 1053-1062 (1972) oder J. Org. Chem 51, 1713-1719 (1986) beschrieben, zu Pilocarpin umgesetzt werden.Compounds of formula I, in particular of formula la, are known and can be prepared by known methods, e.g. in Helv. Chim. Acta 5J5, 1053-1062 (1972) or J. Org. Chem 51, 1713-1719 (1986), can be converted to pilocarpine.
Die nach dem erfindungsgemäßen Verfahren herstellbaren 5-gliedrigen, stickstoffhaltigen Heterocyclen sind darüber- hinaus wertvolle Ausgangsstoffe für die Herstellung von Farbstoffen, Pflanzenschutzmitteln und weiteren Pharma- zeutika oder eignen sich selbst, wie z.B. in EP-OS 0207563 offenbart, als Mittel zum Beeinflussen des Pflanzenwachs¬ tums.The 5-membered, nitrogen-containing heterocycles which can be prepared by the process according to the invention are also valuable starting materials for the production of dyes, crop protection agents and other pharmaceuticals or are themselves suitable, such as, for example, in EP-OS 0207563, as a means of influencing plant growth.
Das erfindungsgemäße Verfahren erlaubt somit die Her- Stellung von Verbindungen der Formel I, insbesondere der Formel la, auf einfache Weise in hohen Ausbeuten aus leicht zugänglichen, wohlfeilen Ausgangsmaterialien in einem einzigen, im Eintopfverfahren durchzuführenden Syntheseschritt und stellt damit einen wesentlichen Fort- schritt auf dem Gebiet der Synthese von Verbindungen der Formel I, insbesondere bei der Pilocarpin-Synthese, dar.The process according to the invention thus allows the preparation of compounds of the formula I, in particular of the formula Ia, in a simple manner in high yields from easily accessible, inexpensive starting materials in a single synthesis step to be carried out in a one-pot process and thus represents a significant step forward in the process Field of synthesis of compounds of formula I, in particular in pilocarpine synthesis.
Die folgenden Beispiele sollen die Erfindung erläutern, ohne sie zu begrenzen: Beispiel 1The following examples are intended to illustrate the invention without limiting it: example 1
In eine unter Stickstoff gehaltene Suspension von 16,21 g Natriummethylat in 300 ml Toluol trägt man bei Raumtem¬ peratur nacheinander 17,45 g Sarcosinmethylester-hydro- chlorid sowie 31,09 g 3-Dimethylamino-2-azaprop-2-en-l- yliden-dimethylammoniumchlorid ein und rührt das Gemisch17.45 g of sarcosine methyl ester hydrochloride and 31.09 g of 3-dimethylamino-2-azaprop-2-en-1 are added in succession to a suspension of 16.21 g of sodium methylate in 300 ml of toluene, kept under nitrogen, at room temperature - Ylidene-dimethylammonium chloride and the mixture is stirred
24 Stunden bei 70 °C. Danach dekantiert man ab, extrahiert den Rückstand dreimal mit Toluol und engt ein.24 hours at 70 ° C. Then decanted off, the residue extracted three times with toluene and concentrated.
Nach Chromatographie des Rückstandes an Kieselgel (Ethyl- acetat) werden 15,1 g l-Methyl-lH-imidazol-5-carbonsäure- methylester erhalten; Kp: 115 °C/8 torr, Sublimation beiAfter chromatography of the residue on silica gel (ethyl acetate), 15.1 g of methyl 1-methyl-1H-imidazole-5-carboxylic acid are obtained; Kp: 115 ° C / 8 torr, sublimation at
25 °C/0,01 torr, F. 56 °C.25 ° C / 0.01 torr, mp 56 ° C.
Analog erhält man mit Bernsteinsäuredi ethylester den Pyrrol-3,4-dicarbonsäure-dimethylester;Analogously, dimethyl pyrrole-3,4-dicarboxylate is obtained with diethyl succinate;
mit N-(9-Fluorenyl)-glycin-methylester-hydrochlorid den 1-(9-Fluorenyl)-lH-imidazol-5-carbonsäuremethylester;with N- (9-fluorenyl) glycine methyl ester hydrochloride, the 1- (9-fluorenyl) 1H-imidazole-5-carboxylic acid methyl ester;
mit N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-glycinmethyl- ester-hydrochlorid den 1-(1,2,3,4-Tetrahydronaphthalen- l-yl)-l-H-imidazol-5-carbonsäuremethylester, F. 63 °C;with N- (1,2,3,4-tetrahydronaphthalene-1-yl) -glycine methyl ester hydrochloride, the 1- (1,2,3,4-tetrahydronaphthalene-l-yl) -lH-imidazole-5-carboxylic acid methyl ester , Mp 63 ° C;
mit N-Methylaminoacetonitril das 1-Methyl-lH-imidazol- 5-carbonitril;with N-methylaminoacetonitrile the 1-methyl-1H-imidazole-5-carbonitrile;
mit N-Benzyl-glycin-benzylester-hydrochlorid den 1-Benzyl- lH-imidazol-5-carbonsäurebenzylester;with N-benzyl-glycine-benzyl ester hydrochloride the 1-benzyl-1H-imidazole-5-carboxylic acid benzyl ester;
mit Natriumethylät/Sarcosinethylester-hydrochlorid erhält man l-Methyl-lH-imidazol-5-carbonsäureethylester; mit N-(9-Fluorenyl)-glycinbenzylester-hydrochlorid erhält man 1-(9-Fluorenyl)-lH-imidazol-5-carbonsäurebenzylester.with sodium ethyl acetate / sarcosine ethyl ester hydrochloride, 1-methyl-1H-imidazole-5-carboxylic acid ethyl ester is obtained; With N- (9-fluorenyl) glycine benzyl ester hydrochloride, 1- (9-fluorenyl) 1H-imidazole-5-carboxylic acid benzyl ester is obtained.
Mit Glycinester-hydrochloriden erhält man analog:Analogously with glycine ester hydrochlorides:
l-H-Imidazol-5-carbonsäuremethylester l-H-Imidazol-5-carbonsäureethylester, F. 158 °C l-H-Imidazol-5-carbonsäurebenzylester1-H-imidazole-5-carboxylic acid methyl ester 1-H-imidazole-5-carboxylic acid ethyl ester, mp 158 ° C. 1-H-imidazole-5-carboxylic acid benzyl ester
Mit N-substituierten Glycinester-hydrochloriden erhält man analog:With N-substituted glycine ester hydrochlorides one obtains analogously:
l-Isopropyl-l-H-imidazol-5-carbonsäuremethylester, Kp 130 °C/13 Torr l-Cyclohexyl-l-H-imidazol-5-carbonsäuremethylester,1-isopropyl-1-H-imidazole-5-carboxylic acid methyl ester, bp 130 ° C./13 torr 1-cyclohexyl-1-H-imidazole-5-carboxylic acid methyl ester,
F 90 °C l-Benzyl-l-H-imidazol-5-carbonsäuremethylester, F 64 °C l-Phenyl-l-H-imidazol-5-carbonsäureethylester, F 81 °C l-(2-Ethylhexyl)-lH-imidazol-5-carbonsäuremethylesterF 90 ° C l-benzyl-lH-imidazole-5-carboxylic acid methyl ester, F 64 ° C l-phenyl-lH-imidazole-5-carboxylic acid ethyl ester, F 81 ° C l- (2-ethylhexyl) -lH-imidazole-5- carboxylic acid methyl ester
Beispiel 2Example 2
Man legt unter Stickstoff bei Raumtemperatur eine Suspen¬ sion von 189,07 g Natriummethylat in 2000 ml Dioxan vor, trägt unter Rühren nacheinander 181,45 g Sarcosinmethyl- ester-Hydrochlorid und 261,84 g 3-Dimethylamino-2-azaprop- 2-en-l-yliden-dimethylammoniumchlorid ein und rührt das Reaktionsgemisch 24 Stunden bei 60 °C.A suspension of 189.07 g of sodium methylate in 2000 ml of dioxane is initially introduced under nitrogen at room temperature, 181.45 g of sarcosine methyl ester hydrochloride and 261.84 g of 3-dimethylamino-2-azaprop-2- en-l-ylidene-dimethylammonium chloride and the reaction mixture is stirred at 60 ° C. for 24 hours.
Danach wird abgesaugt, mit Dioxan nachgewaschen und das Filtrat eingeengt.It is then suctioned off, washed with dioxane and the filtrate is concentrated.
Nach Chromatographie des Rückstandes an Kieselgel (Ethyl- acetat) werden 152,1 g l-Methyl-lH-imidazol-5-carbonsäure- methylester, F. 55 °C bis 56 °C erhalten. H-NMR (200 MHz, CDC13): 6 = 7,72 (brs, 1H); 7,55 (brs, 1H); 3,90 (s, 3H); 3,84 (s, 3H) .After chromatography of the residue on silica gel (ethyl acetate ) , 152.1 g of methyl lH-imidazole-5-carboxylic acid methyl ester, melting point 55 ° C. to 56 ° C., are obtained. H NMR (200 MHz, CDC1 3 ): 6 = 7.72 (brs, 1H); 7.55 (brs, 1H); 3.90 (s, 3H); 3.84 (s, 3H).
Beispiel 3Example 3
Man legt unter Stickstoff bei Raumtemperatur eine Sus- spension von 54,03 g Natriummethylat in 600 ml Dioxan vor, trägt nacheinander 41,87 g Sarcosinmethylester- Hydrochlorid, 65,46 g 3-Dimethylamino-2-azaprop-2-en- 1-yliden-dimethylammoniumchlorid sowie 47,24 g Oxal- säuredimethylester ein und rührt das Reaktionsgemisch 12 Stunden bei 65 °C. Danach wird über Kieselgur abge¬ saugt, mit Dioxan nachgewaschen und unter vermindertem Druck eingeengt.A suspension of 54.03 g of sodium methylate in 600 ml of dioxane is introduced under nitrogen at room temperature, and 41.87 g of sarcosine methyl ester hydrochloride, 65.46 g of 3-dimethylamino-2-azaprop-2-ene 1- are carried in succession. ylidene-dimethylammonium chloride and 47.24 g of dimethyl oxalate and the reaction mixture is stirred at 65 ° C. for 12 hours. It is then suctioned off through diatomaceous earth, washed with dioxane and concentrated under reduced pressure.
Nach Chromatographie des Rückstandes an Kieselgel (Ethyl- acetat) werden 33,2 g l-Methyl-lH-imidazol-5-carbonsäure- methylester mit einem Schmelzpunkt von 55 °C erhalten.After chromatography of the residue on silica gel (ethyl acetate), 33.2 g of methyl 1-methyl-1H-imidazole-5-carboxylic acid with a melting point of 55 ° C. are obtained.
Beispiel 4Example 4
In eine unter Stickstoff gehaltene Suspension von 16,21 g Natriummethylat in 200 ml Tetrahydrofuran trägt man bei Raumtemperatur nacheinander 13,96 g Sarcosinmethylester- Hydrochlorid und 21,27 g 3-Dimethylamino-2-azaprop-2-en- 1-yliden-dimethylammoniumchlorid ein und rührt das Ge¬ misch 6 Stunden bei Rückflußtemperatur.In a nitrogen-containing suspension of 16.21 g of sodium methylate in 200 ml of tetrahydrofuran, 13.96 g of sarcosine methyl ester hydrochloride and 21.27 g of 3-dimethylamino-2-azaprop-2-en-1-ylidene-dimethylammonium chloride are added in succession at room temperature and the mixture is stirred for 6 hours at reflux temperature.
Danach kühlt man auf Raumtemperatur ab, filtriert über Kieselgur, wäscht mit Tetrahydrofuran nach und engt unter vermindertem Druck ein. Nach Chromatographie des Rückstandes an Kieselgel (Ethyl- acetat) werden 11,3 g l-Methyl-lH-imidazol-5-carbonsäure- methylester erhalten; Fp. 55-56 °C.The mixture is then cooled to room temperature, filtered through diatomaceous earth, washed with tetrahydrofuran and concentrated under reduced pressure. After chromatography of the residue on silica gel (ethyl acetate), 11.3 g of methyl l-methyl-1H-imidazole-5-carboxylic acid are obtained; Mp 55-56 ° C.
Beispiel 5Example 5
Man legt unter Stickstoff bei Raumtemperatur eine Suspen¬ sion von 162 g Natriummethylat in 2000 ml Dioxan vor, trägt unter Rühren nacheinander 139,6 g Sarcosinmethyl- ester-Hydrochlorid und 212,7 g 3-Dimethylamino-2-azaprop- 2-en-l-yliden-dimethylammoniumchlorid ein und rührt das Reaktionsgemisch 24 Stunden bei 90 °C.A suspension of 162 g of sodium methylate in 2000 ml of dioxane is initially introduced under nitrogen at room temperature, 139.6 g of sarcosine methyl ester hydrochloride and 212.7 g of 3-dimethylamino-2-azaprop-2-ene are carried in succession with stirring. l-ylidene-dimethylammonium chloride and the reaction mixture is stirred at 90 ° C. for 24 hours.
Danach wird abgesaugt, mit Dioxan nachgewaschen und das Filtrat unter vermindertem Druck eingeengt.It is then suctioned off, washed with dioxane and the filtrate is concentrated under reduced pressure.
Nach Destillation des Rückstandes im Vakuum werden 89,3 g l-Methyl-lH-imidazol-5-carbonsäuredimethylamid erhalten; F. 46-47 °C.After distilling the residue in vacuo, 89.3 g of l-methyl-1H-imidazole-5-carboxylic acid dimethylamide are obtained; F. 46-47 ° C.
Beispiel 6Example 6
Zu einem unter Stickstoff gehaltenen Gemisch aus Lithiu - diisopropylamid (hergestellt aus 3,0 g Diisopropylamin und 19 ml einer 15%igen Lösung von n-Butyllithium in Hexan) und 15 ml Tetrahydrofuran gibt man bei -78 °C ein Gemisch von 4,5 g Bernsteinsäuredibenzylester und 10 ml Tetrahydro¬ furan. Nach Aufwärmen auf 0 °C gibt man 3,1 g 3-Dimethyl- amino-2-azaprop-2-en-l-yliden-dimethylammoniumchlorid hinzu und rührt das Gemisch 24 Stunden bei Siedetempera- tur. Nach Zugabe von 25 ml einer gesättigten Ammonium- ehlorid-Lösung extrahiert man die wässrige Phase dreimal mit Ether und engt ein. Nach Chromatographie des Rück¬ standes an Kieselgel (Ethylacetat) erhält man Pyrrol-3,4- dicarbonsäurebenzylester.A mixture of 4.5 is added at -78 ° C. to a mixture of lithium diisopropylamide (made from 3.0 g of diisopropylamine and 19 ml of a 15% solution of n-butyllithium in hexane) and 15 ml of tetrahydrofuran, which is kept under nitrogen g of succinic acid dibenzyl ester and 10 ml of tetrahydrofuran. After warming up to 0 ° C., 3.1 g of 3-dimethylamino-2-azaprop-2-en-1-ylidene-dimethylammonium chloride are added and the mixture is stirred for 24 hours at boiling temperature. After adding 25 ml of a saturated ammonium ehlorid solution, the aqueous phase is extracted three times with ether and concentrated. Chromatography of the residue on silica gel (ethyl acetate) gives benzene pyrrole-3,4-dicarboxylate.
Analog werden dargestelltAnalog are shown
Pyrrol-3,4-dicarbonsäuremethylester Pyrrol-3, -dicarbonsäureethylester Pyrrol-3,4-dicarbonsäureisopropylester 4-Cyanopyrrol-3-carbonsäuremethylester 3,4-Dicyanopyrrol Pyrrole-3,4-dicarboxylic acid methyl ester Pyrrole-3, -dicarboxylic acid ethyl ester Pyrrole-3,4-dicarboxylic acid isopropyl ester 4-cyanopyrrole-3-carboxylic acid methyl ester 3,4-dicyanopyrrole
Anwendungsbeispiel AExample of use A
Kalium-hydrid (4,15 g, 35%ige Öl-Suspension) wird 2mal mit 15 ml Hexan gewaschen und in 150 ml Diethylenglykol suspen¬ diert. Zu diesem Gemisch gibt man bei.0 °C 11,6 g Diethyl- (cyan(1-(tert-butoxycarbonyl)-propyl)-methyl)-phosphonat (hergestellt nach Lit. ) . Nach lstündigem Rühren bei Raum¬ temperatur gibt man ein Gemisch aus 4,0 g 1-Methyl-l-H-imi- dazol-5-carboxaldehyd (hergestellt aus 1-Methyl-l-H-imida- zolcarbonsäuremethylester Jnach Lit.2) und 20 ml Diethylen- glykol hinzu und rührt 12 Stunden bei Raumtemperatur. Nach Zugabe von Wasser und Trennen der Phasen wird die wässrige Phase 3mal mit 200 ml Ether extrahiert. Nach Einengen er¬ hält man ein E/Z-Gemisch von 3-Cyan-2-ethyl-4-(l-methyl- lH-5-imidazolyl)-3-butensäure-tert.-butylester. Aus diesem erhält man nach Lit. in 5 Stufen (+)-Isopilocarpin (F. 159 °C, D = +34,3° (c = 1,"804, Wasser) nach Überführung in das Nitrat), aus dem (+) Pilocarpin durch Epimerisierung erhalten wird:Potassium hydride (4.15 g, 35% oil suspension) is washed twice with 15 ml of hexane and suspended in 150 ml of diethylene glycol. 11.6 g of diethyl (cyan (1- (tert-butoxycarbonyl) propyl) methyl) phosphonate (prepared according to Ref.) Are added to this mixture at 0 ° C. After stirring for 1 hour at room temperature, a mixture of 4.0 g of 1-methyl-1H-imidazole-5-carboxaldehyde (prepared from 1-methyl-1H-imidazolecarboxylic acid methyl ester J according to Ref. 2) and 20 ml Add diethylene glycol and stir for 12 hours at room temperature. After adding water and separating the phases, the aqueous phase is extracted 3 times with 200 ml of ether. After concentration, an E / Z mixture of 3-cyano-2-ethyl-4- (1-methyl-1H-5-imidazolyl) -3-butenoic acid tert-butyl ester is obtained. According to Ref. In 5 steps (+) - isopilocarpine (F. 159 ° C, D = + 34.3 ° (c = 1, "804, water) after conversion into the nitrate), from which (+ ) Pilocarpine is obtained by epimerization:
Zu einer Lösung von 0,21 ml Diisopropylamin in Tetrahydro- furan gibt man bei 0 °C 0,97 ml einer 15%igen Lösung von n- Butyllithium in Hexan. Nach 15minütigem Rühren und Abkühlen auf -78 °C fügt man 100 mg (+)-Isopilocarpin gelöst in 1 ml Tetrahydrofuran hinzu und rührt 10 Stunden bei -78 °C. Nach Zugabe von 1 g 2,6-Di-tert-butyl-4-methylphenol, Aufwärmen auf Raumtemperatur und Hinzufügen von 15 ml Salzsäure (0,5 n) werden die Phasen getrennt. Die wässrige Phase wird 2mal mit 25 ml Chloroform gewaschen. Nach Einengen der organischen Phase und präparativer Trennung an einer HPLC-Säule erhält man optisch reines (+)-Pilocarpin, das mit Salpetersäure (65%ig) in Ethanol in das Pilocarpinnitrat, F. 174 °C, αD = +81° (c = 1,618, Wasser), übergeführt wird. Lit. : R.S. Compagnone, H. Rapoport, J. Org. Chem. 51, 1713-1719 (1986)0.97 ml of a 15% solution of n-butyllithium in hexane is added at 0 ° C. to a solution of 0.21 ml of diisopropylamine in tetrahydrofuran. After stirring for 15 minutes and cooling to -78 ° C., 100 mg (+) - isopilocarpine dissolved in 1 ml of tetrahydrofuran are added and the mixture is stirred at -78 ° C. for 10 hours. After adding 1 g of 2,6-di-tert-butyl-4-methylphenol, warming up to room temperature and adding 15 ml of hydrochloric acid (0.5 N), the phases are separated. The aqueous phase is washed twice with 25 ml of chloroform. After concentrating the organic phase and preparative separation on an HPLC column, optically pure (+) - pilocarpine is obtained, which is mixed with nitric acid (65%) in ethanol in the pilocarpine nitrate, F. 174 ° C, α D = + 81 ° ( c = 1.618, water). Lit .: RS Compagnone, H. Rapoport, J. Org. Chem. 51, 1713-1719 (1986)
2 Lit. : H. Link, K. Bernauer, Helv. Chim. Acta 55_,2 Lit.: H. Link, K. Bernauer, Helv. Chim. Acta 55_,
1053-1062- (1972) 1053-1062- (1972)

Claims

Patentansprüche Claims
1. Verfahren zur Herstellung von Verbindungen der Formel I1. Process for the preparation of compounds of formula I.
worinwherein
A NR1 oder CH-X2,A NR 1 or CH-X 2 ,
X 1 und X2 jewei.ls unabhängi•g voneinander CO-OR2, C0-NR3R4 oder CN,X 1 and X2 are each independent of one another • CO-OR2, C0-NR 3 R 4 or CN,
R 1 und R2 jewei.ls unabhängig voneinander Wasser¬ stoff, Alkyl mit 1-8 C-Atomen oder einen carbocyclischen Rest, undR 1 and R2 each independently of one another are hydrogen, alkyl having 1-8 C atoms or a carbocyclic radical, and
3 4 . . . . 3 4. , , ,
R und R jeweils unabhängig voneinander Alkyl mit 1-7 C-Atomen, Aryl mit 6-8 C-Atomen oderR and R each independently of one another alkyl with 1-7 C atoms, aryl with 6-8 C atoms or
Aralkyl mit 7-13 C-Atomen oder auch je¬ weils zusammen mit dem benachbarten Stick¬ stoffatom einen heterocyclischen Rest mit 2-6 C-Atomen, wobei auch eine CH^-Gruppe durch 0, S oder NH ersetzt sein kann, bedeuten, dadurch gekennzeichnet, daß man eine Methylen-Verbindung der Formel IIAralkyl having 7-13 C atoms, or in each case together with the adjacent Stick¬ atom a heterocyclic radical with 2-6 C atoms, where one CH ^ group is replaced by 0, S or NH may be replaced, mean, characterized in that a methylene compound of formula II
X -CH2-AH IIX -CH 2 -AH II
oder deren Säure-Additions-Salz, worin X und A die angegebene Bedeutung besitzen, mit einem N,N' tetrasubstituierten Aminomethylenformamidinium¬ Salz der Formel III ,or their acid addition salt, in which X and A have the meaning given, with an N, N'-tetrasubstituted aminomethyleneformamidinium salt of the formula III,
worinwherein
R 3 und R4 die angegebene Bedeutung besitzen, undR 3 and R4 have the meaning given, and
Yθ Clθ, Brθ, Jθ, J®, Clθ| oder BF^ bedeutet,Y θ Cl θ , Br θ , J θ , J ® , Clθ | or BF ^ means
und einer Base umsetzt.and implement a base.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß A NR bedeutet und daß die Verbindung der For¬ mel II in Form eines Säure-Additions-Salzes mit einer Verbindung der Formel III umgesetzt wird.2. The method according to claim 1, characterized in that A is NR and that the compound of formula II in the form of an acid addition salt is reacted with a compound of formula III.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekenn- zeichnet, daß man als Base Metallalkoholate verwen¬ det.3. The method according to claim 1 or 2, characterized in that one uses as the base metal alcoholates.
4. Verfahren zur Herstellung der Verbindungen der For- mel I, worin X 1 CO-OR2 bedeutet, nach Anspruch 2 oder 3, dadurch gekennzeichnet, daß man die Reak- tion in Gegenwart eines nicht-enolisierbaren Car¬ bonsäureesters durchführt. 4. A process for the preparation of the compounds of the formula I, in which X 1 is CO-OR2, according to claim 2 or 3, characterized in that the reaction is carried out in the presence of a non-enolizable carboxylic acid ester.
5. Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß man als nicht-enolisierbaren Carbonsäureester Oxalsäuredimethylester einsetzt.5. The method according to claim 4, characterized in that the non-enolizable carboxylic acid ester used is dimethyl oxalate.
6. Verwendung der Verbindungen der Formel I zur Her¬ stellung von Pilocarpin, dadurch gekennzeichnet, daß die nach mindestens einem der Ansprüche 1-5 herge¬ stellte Verbindung der Formel I in an sich bekann¬ ter Weise zu Pilocarpin umsetzt wird. 6. Use of the compounds of the formula I for the preparation of pilocarpine, characterized in that the compound of the formula I prepared according to at least one of claims 1-5 is reacted to pilocarpine in a manner known per se.
EP89904057A 1988-04-07 1989-03-25 Process for producing 5-member nitrogen-containing hetero-aromatic compounds Pending EP0362350A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3811621A DE3811621A1 (en) 1988-04-07 1988-04-07 METHOD FOR PRODUCING 1H-IMIDAZOLE-5-CARBONIC ACID ESTERS OR NITRILES AND PYRROL-3,4-CARBONIC ACID ESTERS OR NITRILES AND USE OF THE PRODUCED COMPOUNDS FOR SYNTHESISING PILOCARPINE
DE3811621 1988-04-07

Publications (1)

Publication Number Publication Date
EP0362350A1 true EP0362350A1 (en) 1990-04-11

Family

ID=6351532

Family Applications (2)

Application Number Title Priority Date Filing Date
EP89105365A Expired - Lifetime EP0336250B1 (en) 1988-04-07 1989-03-25 Process for the preparation of 5-members-n-containing heteroaromates
EP89904057A Pending EP0362350A1 (en) 1988-04-07 1989-03-25 Process for producing 5-member nitrogen-containing hetero-aromatic compounds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP89105365A Expired - Lifetime EP0336250B1 (en) 1988-04-07 1989-03-25 Process for the preparation of 5-members-n-containing heteroaromates

Country Status (15)

Country Link
US (1) US5075452A (en)
EP (2) EP0336250B1 (en)
JP (2) JP2805230B2 (en)
KR (1) KR0122131B1 (en)
CN (1) CN1022920C (en)
AT (1) ATE80388T1 (en)
AU (1) AU616962B2 (en)
CA (1) CA1338787C (en)
DE (2) DE3811621A1 (en)
ES (1) ES2052797T3 (en)
HU (1) HU202214B (en)
IE (1) IE63676B1 (en)
IL (1) IL89860A0 (en)
WO (1) WO1989009768A1 (en)
ZA (1) ZA892516B (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4033612A1 (en) * 1990-10-23 1992-04-30 Merck Patent Gmbh METHOD FOR PRODUCING RACEMIC PILOSININE DERIVATIVES
JPH0641067A (en) * 1992-04-20 1994-02-15 Kitasato Inst:The New calpain-inhibitor kp-1241 and its production
GB9220068D0 (en) * 1992-09-23 1992-11-04 Smithkline Beecham Corp Process
US5565577A (en) * 1992-09-23 1996-10-15 Smithkline Beecham Corporation Process for preparing 1-alkyaryl-2-alkyl-5-formylimidazole
AU5862398A (en) * 1997-01-13 1998-08-03 Lonza A.G. Process for preparing substituted pyrimidine derivatives
CN1086189C (en) * 1997-06-12 2002-06-12 食品机械和化工公司 Ultra-fine microcrystalline cellulose compositions and process for their manufacture
CN101397274B (en) * 2008-10-22 2012-06-27 江苏先声药物研究有限公司 Novel natural imidazole formic acid derivates, preparation method and use thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1184709A (en) * 1957-09-21 1959-07-24 Cfmc New imidazole derivatives, usable as protection agents against ultraviolet rays and their manufacturing processes
GB8516573D0 (en) * 1985-07-01 1985-08-07 Janssen Pharmaceuticaa Nv Controlling weeds
JPS61178968A (en) * 1985-12-13 1986-08-11 Nippon Carbide Ind Co Ltd Production of 1-substituted imidazole-5-carboxamide derivative
JP2562872B2 (en) * 1986-01-25 1996-12-11 四国化成工業 株式会社 Method for synthesizing cyano-imidazole compound
DE3729852A1 (en) * 1987-09-05 1989-03-23 Basf Ag METHOD FOR PRODUCING 1-ALKYLIMIDAZOLE-5-CARBONIC ACIDS AND ITS ESTERS, AMIDES AND NITRILES

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8909768A1 *

Also Published As

Publication number Publication date
HU202214B (en) 1991-02-28
CA1338787C (en) 1996-12-10
ATE80388T1 (en) 1992-09-15
AU3364289A (en) 1989-11-03
IE891101L (en) 1989-10-07
IE63676B1 (en) 1995-05-31
DE58902228D1 (en) 1992-10-15
JP2805230B2 (en) 1998-09-30
KR0122131B1 (en) 1997-11-13
CN1022920C (en) 1993-12-01
DE3811621A1 (en) 1989-10-26
CN1037896A (en) 1989-12-13
WO1989009768A1 (en) 1989-10-19
HU892146D0 (en) 1990-02-28
JPH02504518A (en) 1990-12-20
KR900700461A (en) 1990-08-13
HUT51258A (en) 1990-04-28
ES2052797T3 (en) 1994-07-16
EP0336250A1 (en) 1989-10-11
ZA892516B (en) 1989-12-27
JPH10182637A (en) 1998-07-07
EP0336250B1 (en) 1992-09-09
AU616962B2 (en) 1991-11-14
JP3226863B2 (en) 2001-11-05
US5075452A (en) 1991-12-24
IL89860A0 (en) 1989-12-15

Similar Documents

Publication Publication Date Title
EP0176846A2 (en) 3-Amino-2-benzoyl-acrylic-acid derivatives and process for their preparation
EP0789019B1 (en) Process for the production of 4-oxoimidazolinium salts
EP0336250B1 (en) Process for the preparation of 5-members-n-containing heteroaromates
EP0380712B1 (en) Process for the preparation of 2,6-dichlorodiphenylaminoacetic-acid derivatives
EP1607090B1 (en) Asimadoline for the treatment of irritable bowel syndrome
EP0234516B1 (en) 1,6-naphthyridine derivatives, process for their preparation and medicine containing them for the treatment of vascular diseases
EP0252353B1 (en) 4-benzyloxy-3-pyrrolin-2-one-1-yl-acetamide, preparation and use
EP0216324B1 (en) 4-alkoxy-3-pyrrolin-2-one-1-yl-acetic acid alkyl and benzyl esters and their preparation
DE69703115T2 (en) Intermediates to produce 2-imidazolin-5one derivatives.
EP0782991B1 (en) Process for the preparation of 2-substituted 5-chloroimidazole-4-carbaldehydes
DE1935404C3 (en) Process for the manufacture of quinazolines
CH653996A5 (en) TRYPTAMINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF.
DE2661028C2 (en)
DE3027619A1 (en) 6-ALKYL-7-PHENYL-1,6-NAPHTYRADINE- 5 (6H) -ON DERIVATIVES
EP0104566B1 (en) Process for the preparation of 5,11-dihydro-11-((4-methyl-1-piperazinyl)-acetyl)-6h-pyrido(2,3-b)(1,4)benzodiazepin-6-one
DE2653251A1 (en) AZABICYCLO SQUARE BRACKET ON 3.1.O SQUARE BRACKET FOR HEXANE DERIVATIVES, THEIR PRODUCTION AND USE
DD247217A5 (en) PROCESS FOR PREPARING 2,6-DIMETHYL-4- (3&#39;-NITROPHENYL) -1,4-DIHYDROPYRIDINE-3,5-DICARBONE ACID-3 BETA (N-BENZYL-N-METHYLAMINO) ETHETYLENE-5-METHYL ESTER AND THE HYDROCHLORIDE SALT
DE2828888C2 (en)
DE69711265T2 (en) Process for the preparation of 5- (alkoxymethyl) -2,3-pyridinedicarboximide compounds
DE19947953A1 (en) Process for the selective cleavage of cyclic carboxylic acid anhydrides
DE2628469B2 (en) Process for the preparation of γ-amino alcohols
EP2554539B1 (en) Method for producing gamma-spirolactams from cyclic unsaturated carboxylic acids
EP0395580A2 (en) Process for the preparation of polycyclic compounds
DE3209081C2 (en)
DE3229046A1 (en) METHOD FOR REVERSING THE CONFIGURATION OF OPTICALLY ACTIVE CONNECTIONS AND OPTICALLY ACTIVE INTERMEDIATE PRODUCTS OF THIS METHOD

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI NL SE

17P Request for examination filed

Effective date: 19900221

XX Miscellaneous (additional remarks)

Free format text: VERFAHREN ABGESCHLOSSEN INFOLGE VERBINDUNG MIT 89105365.4/0336250 (EUROPAEISCHE ANMELDENUMMER/VEROEFFENTLICHUNGSNUMMER) VOM 06.08.91.