Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-12-06
1991-12-24
Lee, Mary C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548528, 548531, 548536, 548537, 548561, 544129, 544130, 544139, 544141, 546187, 546208, 546210, C07D23390, C07D20734, C07D40506
Patent
active
050754521
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for the preparation of compounds of the formula I ##STR2## in which A is NR.sup.1 or CH--X.sup.2, CO--NR.sup.3 R.sup.4 or CN, having 1-8 C atoms or a carbocyclic radical and C atoms, aryl having 6-8 C atoms or aralkyl having 7-13 C atoms or are each together with the adjacent nitrogen atom also a heterocyclic radical having 2-6 C atoms, in which a CH.sub.2 group can also be replaced by O, S or NH.
The object of the invention was to provide a novel process for the preparation of compounds of the formula I which makes these compounds available by means of simple reactions in a high yield.
Compounds of the formula I are useful synthetic intermediates; the compounds of the formula Ia ##STR3## in which R.sup.1 and X.sup.1 have the meaning mentioned are used in particular in the synthesis of imidazole alkaloids such as, for example, isomacrorine or pilocarpine.
Ia (X.sup.1 =COOR.sup.2) can be prepared according to EP-OS 0,207,563 in 4 steps starting from N-alkylglycine ester hydrochlorides.
Starting from diethyl N-methylacetaminomalonate, Ia (R.sup.1 =CH.sub.3, X.sup.1 =COOR.sup.2) is obtained in a 5-step synthesis.
In another 5-step synthesis, diaminomaleonitrile can be reacted with triethyl orthoformate to give the imidazole-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.sup.1 =CH.sub.3, X.sup.1 =COOH).
However, all these processes are characterized by a large number of synthetic steps and accordingly a low total yield.
Although it is known that 1,3,4-triazoles are obtained by reaction of 3-dimethylamino-2-azaprop-2-en-1-ylidene-dimethylammonium chloride (Gold's reagent) with hydrazines, no mention is made of the fact that this reagent can also be used for the preparation of other 5-membered heterocycles.
Surprisingly, it has now been found that compounds of the formula I, in particular of the formula Ia, can be prepared by reaction of methylene compounds of the formula II or acid addition salts thereof with aminomethyleneformamidinium salts of the formula III in a single synthetic step, in a one-pot process and in high yields.
The invention accordingly relates to a process for the preparation of compounds of the formula I ##STR4## in which A is NR.sup.1 or CH--X.sup.2, CO--NR.sup.3 R.sup.4 or CN, having 1-7 C atoms or a carbocyclic radical and C atoms, aryl having 6-8 C atoms or aralkyl having 7-13 C atoms or are each together with the adjacent nitrogen atom also a heterocyclic radical having 2-6 C atoms, in which a CH.sub.2 group can also be replaced by O, S or NH, mentioned is reacted with a salt of the formula III ##STR5## in which R.sup.3 and R.sup.4 have the meaning mentioned and I.sub.3.sup..crclbar., ClO.sub.4.sup..crclbar. or BF.sub.4.sup..crclbar.,
The invention in particular relates to a process for the preparation of compounds of the formula Ia in which A is NR.sup.1, and the compound of the formula IIa is reacted in the form of an acid addition salt with a compound of the formula III.
The invention also 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 compounds in medicaments, in particular pilocarpine.
The process according to the invention gives, regardless of the nature of groups A, X.sup.1, X.sup.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X.sup..crclbar., the corresponding compounds of the formula I without exception in high yields.
If A is NR.sup.1 and X.sup.1 is COOR.sup.2, R.sup.1 and R.sup.2 are each
independently of one another hydrogen, alkyl having 1-7 C atoms or are carbocyclic radicals.
If R.sup.1 and/or R.sup.2 are an alkyl radical, this radical can be straight-chain or branched. Accordingly, it is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, i-propyl, 1-(or 2)methyl-propyl, tert.-butyl, 1-(2- or 3-)methylbutyl, neo-pentyl, 1-(2-, 3- or 4-)-methylpentyl or 1-(2-, 3-, 4- or 5-)methylhe
Basedow Arno
Casutt Michael
Kirchlechner Richard
Lee Mary C.
Merck Patent Gesellschaft mit beschrankter Haftung
Miltenberger Lenora
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