Method for producing salts of cyclic amidines

Details Method for producing salts of cyclic amidines Method for producing salts of cyclic amidines

2000-06-07

2001-09-04

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S245000, C548S531000

Reexamination Certificate

active

06284892

ABSTRACT:

The present invention relates to a process for the production of compounds of the general formula (I)
wherein X
⊖
represents an inorganic anion, m=1, 2 or 3, and R represents a linear (C
1
-C
4
)-alkyl radical.
Compounds of the above structural type are advantageous intermediates for the production of bioactive ingredients such as are known from U.S. Pat. No. 4,213,773 and WO 94/22828.
WO 94/22828 describes the possibility of cyclising N-(4-cyanobutyl) carbamic acid alkyl esters by means of an anhydrous hydrogen halide. The yields of the latter reaction are not mentioned. A paper published in Synthesis 1984, 831 is referred to for the production of the N-(4-cyanobutyl) carbamic acid alkyl ester. However, the process indicated therein affords only a maximum 32% yield of the latter compound. That is to say that according to the prior art the maximum possible total yield of the production of (I), when m=2 and R=Me, is 32%. Furthermore, a mercury salt is used in the latter process, for ecological reasons a practical impossibility on a large industrial scale. In order to produce N-(4-cyanobutyl) carbamic acid methyl ester it is necessary according to the Synthesis process to pass the ethene which is to be used through a liquid solution of methyl carbamate and mercury nitrate in dichloromethane, which is under reflux. Apart from the tendency of ethene to polymerise when in contact with Lewis acids or Lewis bases and radicals, the storage of this high-risk chemical, necessary for a large-scale industrial operation, is extremely questionable. the object of the invention was consequently to find a process for the production of compounds of the general formula (I), which improves on the prior art as regards both economic and ecological considerations and affords a lower-risk, stable process sequence on a large industrial scale.
The latter and other objects not further specified are achieved by a process in accordance with the features of the characterising part of claim
1
. Particularly advantageous embodiments of the process are provided by the sub-claims dependent on claim
1
.
Very good total yields of >70% of the desired compounds are achieved in a robust process without the occurrence of ecologically questionable wastes, as a result of the reaction of a corresponding enantiomer-pure or racemic &ohgr;-amino-&agr;-amino acid in selective manner at the &ohgr;-amino function thereof to give compounds of the general formula (II)
oxidative decarboxylation of the compounds (II) thus obtained to give substances of the general formula (III)
and reaction of the compound (III) with the exclusion of water in the presence of an acid, with ring closure, to give the salt of the general formula (I)
It is a further advantage of the latter process that all the solvent streams can be largely circulated, thus reducing the volume of unavoidable waste to the maximum possible degree.
It is particularly advantageous to react the corresponding &ohgr;-amino-&agr;-amino acid or a precursor of the latter carboxylic acid, under basic conditions with a reagent of the general formula (IV)
wherein Y=Cl, Br or OMe or
and R=(C
1
-C
4
)-alkyl present preferably in linear form, or aryl, to give compounds of the general formula (II). Precursors of &ohgr;-amino-&agr;-amino acids, which are considered here are commercially obtainable hydrochlorides and hydrates thereof or compounds in the form of their free bases as approximately 50% aqueous solutions. In a particularly preferred case the &ohgr;-amino-&agr;-aminocarboxylic acid is lysine. Such reactions are in principle known from Houben-Weyl 1977, Vol. XV/I, pp. 468 et seq., but the use of dimethyl carbonate (DMC) is particularly advantageously suitable for affording exceptionally highly selective protection to the &ohgr;-amino-&agr;-amino acid only at its &ohgr;-amino function.
The choice may be made to introduce the latter protective group in a two-phase system prepared from water and a water-immiscible organic solvent. In this case organic solvents which have proved valuable are aliphatic hydrocarbons, chlorinated hydrocarbons and aromatic hydrocarbons, or ethers and ketones. Suitable aliphatic hydrocarbons are n-pentane, n-hexane, n-heptane, cyclopentane, cyclohexane, methylcyclohexane, petroleum ether, ligroin.
Particularly suitable chlorinated/brominated hydrocarbons are chloroform, methylene chloride, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,2-dichloroethane, bromoform, dibromomethane, 1,2-dibromoether.
Suitable aromatic hydrocarbons are toluene, 1,2-, 1,3-, 1,4-xylene, mesitylene.
Ethers which are considered are diethyl ether, methyl tert.-butyl ether, 1,2-diethoxyethylene.
Particularly preferred ketones are methyl isobutyl ketone, diethyl ketone, diisopropyl ketone, tert.-butyl methyl ketone.
An advantageous embodiment of the aforementioned process is likewise formed by the reaction of &ohgr;-amino-&agr;-amino acids, or a precursor of the latter carboxylic acids in a single-phase system prepared from water with the reagent of the general formula (IV), the use of DMC is particularly advantageous. A water-miscible organic solvent may optionally be added to the latter system. The following have proved to be suitable water-miscible organic solvents: alcohols such as, for example, methanol, ethanol, isopropanol, propanol, tert.-butanol, sec-butanol, isobutanol, glycol. Further water-miscible organic solvents are ethers such as, for example, THF, 1,2-dimethoxyethane or diethylene glycol, dioxane.
When DMC is used as the acylation reagent in the aforementioned reaction it is advantageous to work with DMC in excess such as to afford the &ohgr;-amino-&agr;-amino acid used the maximum possible &ohgr;-protection. The excess may be up to 10 times the equivalent quantity of DMC compared with the &ohgr;-amino-&agr;-amino acid. An excess of 3-5 eq. is particularly preferred.
It is advantageous to introduce the (&ohgr;-amino-&agr;-amino acids or the precursors of the latter carboxylic acids as an aqueous basic solution and dispense the DMC diluted with an organic solvent into the solution, or to admix the DMC as such. If organic diluents are used, the single-phase or two-phase systems described above then arise, depending on whether the latter are water-miscible or water-immiscible. The use of DMC pure always results in a single-phase system.
Advantageously, the unused excess of DMC collects in the organic, upper phase, when a two-phase reaction medium is used, and can be recycled in simple manner by phase separation without the risk of excessive saponification in the aqueous basic, lower phase.
In order to reduce DMC saponification as far as possible and achieve short reaction times and high yields, it is always advantageous to work with very thorough intermixing of the two phases. This correspondingly thorough mixing can be achieved by particular stirrer units or pumps such as, for example, regenerative pumps, jet mixers, nozzle systems, venturi mixers or ejector pumps, and the like. When the single-phase working method is used, the DMC is introduced into the basic aqueous solution of &ohgr;amino-&agr;-amino acid or the precursor of the latter carboxylic acid, with equally thorough intermixing. It is advantageous here to isolate the excess DMC after the reaction by extracting it with a water-immiscible organic solvent, and to recycle it. The DMC thus recovered can be used again in a subsequent working cycle.
In order to reduce to the greatest possible extent the—hydrolysis—reaction which competes with the introduction of the protective group, the &ohgr;-amino-&agr;-amino acid is reacted with the DMC within the pH range >8 to <14, preferably 10-13, and most particularly preferably 11-12. The following may be used as bases which are useful for adjusting the pH: alkali metal/alkaline earth metal bases or amine derivatives. NaOH, KOH, Ca(OH)
2
, Ba(OH)
2
, Na
2
CO
3
, NaHCO
3
, K
2
CO
3
, KHCO
3
or NH
4
OH, (NH
4
)
2
CO
3
, NH
4
HCO
3
preferably serve to regulate pH in this reaction.
The reaction temperatures

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