Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-09
2002-04-30
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06380391
ABSTRACT:
The present invention relates to a process for the preparation of bis(4-amino-1-pyridinium)alkanes (BAPA) by reacting difunctionalized alkanes with 4-aminopyridines. The invention further relates to the use in products, in particular body hygiene products, to which the BAPA prepared by the process according to the invention have been added.
U.S. Pat. No. 4,206,215 discloses the preparation of BAPA in inert solvents, such as a lower alkanol, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, toluene or xylene at a temperature from 80 to 150° C. for a period of from 1 to 24 hours, and also the reaction in the absence of a solvent by heating stoichiometric amounts of the reaction components for from about 2 to 5 hours at 120 to 150° C. Aprotic solvents and similar reaction conditions are described by Bailey et al. in J. Med. Chem. 1984, 27, 1457-64.
However, the known processes for the preparation of BAPA have numerous disadvantages:
1. The use of organic solvents (in the process preferred in the prior art these are toxicologically unacceptable solvents such as acetonitrile, and N,N-dimethylformamide, which is injurious to health, and, in particular, hazardous for reproduction) is associated with particular technical problems during the preparation, e.g. risk of explosion etc.
2. The use of organic solvents increases the preparation costs since the solvents have to be heated, processed and disposed of, all of which require energy.
3. The relatively high reaction temperature promotes the increased formation of byproducts, noticeable from the discoloration of the reaction mixtures during the reaction, and the products resulting therefrom are likewise coloured.
4. These byproducts and also the contaminations with solvents introduced as a result of the obligatory use of toxicologically unacceptable reaction media, have to be removed in purification steps which are costly (in terms of energy). These obligatory purification steps make the known processes less interesting from an economical viewpoint.
5. The use of the high requirements placed on the purity of the BAPA, expensive quality controls have to be carried out in all process steps.
6. If the process is carried out in accordance with the prior art in health-injurious, in particular reproduction-hazardous dimethylformamide, then a yield of, for example, 77% can be achieved (see Example 6).
7. If the reaction is carried out in toxicologically acceptable acetone, then no product can be isolated in a noteworthy amount (see Example 9).
8. The formation of byproducts and the unsatisfactory yield lead to losses of expensive starting materials, starting firstly during the reaction and secondly during purification.
Accordingly, the object of the present invention was to develop a simple process for the preparation of BAPA which does not have the above-mentioned disadvantages. This preparation process should be advantageous particularly from a production efficiency viewpoint. Because BAPA, inter alia, are used in pharmaceutical and body hygiene products etc., and the corresponding specifications have to be satisfied, they must also be free from traces of any toxicologically unacceptable impurity, which can originate, for example, from the solvent used.
Surprisingly this object is achieved by the process according to the invention for the preparation of BAPA which is carried out in the reaction medium of water or a mixture of water and solvent. According to the process of the invention, yields greater than 80%, even greater than 90%, are possible.
The invention relates to process for the preparation of bis(4-amino-1-pyridinium)alkanes of the formula I
by reacting difunctionalized alkanes of the general formula II
A—Y—A′ (II),
in which Y is a linear or branched alkylene group having 4 to 18 carbon atoms, and A and A′ are identical or different and are a reactive functional group,
with 4-aminopyridines of the general formula III
in which R is linear or branched and is an alkyl, cycloalkyl or alkylaryl group having 5 to 18 carbon atoms,
in a reaction medium and is characterized in that the reaction medium is water or a mixture of water and an organic solvent which comprises at least 10% by weight of water.
Preferred reactive functional groups A and A′ are chlorine, bromine, iodine, methanesulphonyloxy, ethanesulphonyloxy, benzenesulphonyloxy or p-toluenesulphonyloxy.
Y is preferably an alkylene group having 6 to 16 carbon atoms, particularly preferably 8 to 14 carbon atoms, for example 10 carbon atoms, such as, for example, a dec-1,10-diyl group.
R is preferably an alkyl, cycloalkyl or alkylaryl group, in particular an alkyl group, having 6 to 15, in particular 8 to 12, carbon atoms, for example an n-octyl group.
The organic solvent of the aqueous reaction medium is chosen from alcohols, glycols, polyols, polyethylene and polypropylene glycols, ethers, glycol mono- and diethers, completely or incompletely etherified polyols and completely or incompletely etherified polyethylene or polypropylene glycols, and mixtures thereof. Preference is given to 1,2-propylene glycol, phenoxypropanols and phenoxyethanol. Particular preference is given to the solvents (or solvent mixtures of) phenoxyethanol, 2-phenoxy-1-propanol and 1-phenoxy-2-propanol. It is, for example, possible to use 2-phenoxy-1-propanol and 1-phenoxy-2-propanol as a mixture, in any desired ratio, preferably 1:100 to 100:1 parts by weight, in particular 30:70 to 99:1 parts by weight, e.g. the commercially available mixture of 85 parts by weight of 2-phenoxy-1-propanol and 15 parts by weight of 1-phenoxy-2-propanol.
The reaction medium of the process according to the invention comprises at least 10% by weight, preferably at least 30% by weight, in particular at least 50% by weight, such as, for example, 70% by weight, and even up to 100% by weight, of water, and accordingly at most 90% by weight, preferably at most 70% by weight, in particular at most 50% by weight, for example 30% by weight, or even down to 0% by weight, of organic solvent. The process according to the invention is advantageous merely because it is not necessary to use any toxicologically unacceptable solvents and, consequently, in the case of the product prepared in accordance with the process of the invention, the removal, even of small amounts, e.g. of less than 1% by weight, of residues of toxicologically acceptable solvents, as is always necessary for the known processes, in order to satisfy the corresponding specifications, is dispensed with.
In a preferred embodiment no organic solvent is present, i.e. the reaction medium is water.
The reaction mixture can further comprise salt, for example potassium chloride or sodium chloride, the addition of salt, as is known, resulting in an increase in the boiling point of the reaction mixture.
The invention further relates to the use of the products prepared by the process according to the invention in an antimicrobial composition, e.g. a body care composition.
The reactants 4-aminopyridine according to formula (III) and difunctionalized alkane according to formula (II) are added to the reaction medium. The resulting reaction mixture preferably comprises at most 80% by weight, in particular at most 65% by weight, e.g. 50% by weight, of reaction medium. In this connection, it is possible for a multiphase system to form, for example a 2-phase system. To increase the rate of the reaction, the reaction product bis(4-amino-1-pyridinium)alkane of the formula I can be added as emulsifier. For a batch size of 0.2 mol of aminopyridine of the formula III, the preferred amount of reaction medium is 5 to 30 ml, in particular 10 to 20 ml, e.g. 15 ml.
The reaction is carried out by heating to 70° C. to 120° C., preferably 80° C. to 110° C., e.g. 100° C., it being possible to carry out the reaction, if desired, under a pressure of from 1 to 20 bar, preferably 2 to 10 bar, e.g. 5 bar, at a temperature which is higher than the boiling temperature of the reaction medium under atmospheric pressure. In a preferred embodiment, the reaction takes
Beilfuss Wolfgang
Gradtke Ralf
Streek Michael
Air Liquide Sante ( International)
Davis Zinna Northington
Young & Thompson
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