Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-11-14
2004-09-21
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C514S643000
Reexamination Certificate
active
06794543
ABSTRACT:
The present invention relates to a novel process for preparing arylpoly-(oxalkyl)benzyldimethylammonium derivatives by reaction of arylpoly-(oxalkyl) compounds with benzyldimethylamine or substituted benzyl-dimethylamines in a suitable solvent.
Some representatives of the compound class of arylpoly(oxalkyl)benzyl-dimethylammonium halides such as benzethonium chloride
or methylbenzethonium chloride
where
R=(CH
3
)
3
C—CH
2
—C(CH
3
)
2
—
have long been used commercially as biocides. These are crystalline powders whose purity requirements are described in various pharma-copeias. Solutions of these crystalline powders are also used. These compounds have bactericidal and fungicidal activity. Their areas of application as active components of formulations are, for example, disinfection in the hospitals sector, in the pharmaceutical sector or in the veterinary and foods sector. They are also used as preservatives for cosmetics such as hair conditioners, cleansing lotions or shampoos, in particular in rinse-off products, and also as odor control agents.
According to Workbook for Organic Synthesis: The Disconnection Approach, Stuart Warren, John Wiley & Sons, 1982, on pages 49 to 51 the preparation of such compounds where Y=H and R′=H according to the prior art is as shown in the equations 1 to 3.
Equation 1:
Equation 2:
Equation 3:
where
R is alkyl
R′ is H, alkyl
Y is H, CH
3
or alkyl
X is Cl, Br.
U.S. Pat. No. 2,098,203 discloses arylpoly(oxalkyl) chlorides of the formula A where Y=H or C
1
- to C
5
-alkyl, R=C
8
- to C
18
-alkyl and R′=H, alkyl or alkoxy. Compounds of this type are the starting materials of the process of the invention.
U.S. Pat. No. 2,170,111 discloses tertiary amines of the formula B and further tertiary amines of similar structure to B. Their preparation takes place in a similar fashion to equation 2 by reaction of arylpoly(oxalkyl) chlorides of the formula A with amines such as dimethylamine, diethylamine, diethanolamine or morpholine, basic workup, washing and subsequent vacuum distillation.
Arylpoly(oxalkyl)benzyldimethylammonium chlorides of the formula C and also similarly substituted quaternary ammonium cations with further anions are disclosed in U.S. Pat. No. 2,115,250. They are obtained by reaction of the tertiary amines of the formula B or tertiary amines with a similar structure to B with alkylating agents such as benzyl chloride, dimethyl sulfate, diethyl sulfate, dimethyl oxalate, methyl iodide or ethyl bromide in a similar fashion to equation 3.
In Journal of the American College of Toxicology, Volume 4, Number 5, 1985 on page 66, the reaction of the required tertiary amines with benzyl chloride at 60 to 80° C. is likewise given as a route to benzethonium chloride and methylbenzethonium chloride.
In view of the complexity of this multistep reaction sequence including the necessary workup steps, and in view of the undesirable stoichiometric precipitation of sodium chloride or similar salts, it is an object of the present invention is to provide a simplified preparative process for arylpoly(oxalkyl)benzyldimethylammonium derivatives, in particular for benzethonium chloride or methylbenzethonium chloride.
This object is surprisingly achieved by a process involving the reaction of arylpoly(oxalkyl) compounds of the formula (2) with benzyldimethylamine or substituted benzyldimethylamines of the formula (3) in a suitable solvent to give the arylpoly(oxalkyl)benzyldimethylammonium derivatives of the formula (1).
The invention therefore provides a process for preparing arylpoly-(oxalkyl)benzyldimethylammonium derivatives of the formula (1)
which comprises reacting compounds of the formulae (2) and (3)
where
X=Br, Cl, R—SO
3
with R=alkyl, alkylaryl
R
1
=H, C
1
- to C
16
-alkyl or O—C
1
- to O—C
16
-alkyl in the ortho, meta or para position,
R
2
=H, C
1
- to C
4
-alkyl or O—C
1
- to O—C
4
-alkyl,
R
3
=H, C
1
- to C
16
-alkyl or O—C
1
- to O—C
16
-alkyl in the ortho, meta or para position, and
n=1, 2, 3 or 4, at temperatures of from 60 to 160° C. in a solvent under the autogenous pressure in the closed reaction vessel.
R
1
is preferably C
4
- to C
12
-alkyl, in particular octyl or isooctyl in the para position. R
2
is preferably H or CH
3
. n is preferably 2. R
3
is preferably H. X is preferably Cl.
When R
1
=(CH
3
)
3
C—CH
2
—C(CH
3
)
2
in the para position, R
2
=H, n=2, R
3
=H, X=Cl, benzethonium chloride is obtained, and when R
1
=(CH
3
)
3
C—CH
2
—C(CH
3
)
2
in the para position, R
2
=CH
3
, n=2, R
3
=H, X=Cl, methylbenzethonium chloride is obtained. The processes for preparing these compounds constitute preferred embodiments of the invention.
Useful solvents for the process of the invention are preferably polar solvents, such as short-chain alcohols having from 1 to 6, preferably from 1 to 4 carbon atoms, which may be mono- or polyhydric, for example methanol, ethanol, isopropanol or monoethylene glycol, their mixtures with water and in particular water itself.
The arylpoly(oxalkyl) compounds of the formula (2) and the benzyldimethyl-amine or the substituted benzyldimethylamines of the formula (3) are preferably used in a molar ratio (2):(3)=1:0.95 to 1:1.05. The reaction is carried out at temperatures in the range from preferably 100 to 140° C., in particular from 115 to 130° C., under the autogenous pressure of the reaction mixture. The reaction times are preferably chosen so that the concentrations of the starting compounds of the formulae (2) and (3) determined by HPLC analysis of samples taken are as low as possible.
The arylpoly(oxalkyl)benzyldimethylammonium derivative of the formula (1) obtained from the reaction can be purified by recrystallization, for example from chloroform, ether, toluene or xylene. The solvent is preferably removed before recrystallization.
When water is used as the particularly preferred solvent in the reaction, the water can be removed for the purposes of workup after the end of the reaction, for example, by azeotropic distillation, vacuum drying, spray drying or fluidized-bed drying. The crude, water-free arylpoly(oxalkyl)-benzyldimethylammonium derivative of the formula (1) can be purified by recrystallization, for example from chloroform, ether, toluene or xylene.
The examples which follow illustrate the invention.
REFERENCES:
patent: 2098203 (1937-11-01), Bruson
patent: 2115250 (1938-04-01), Bruson
patent: 2170111 (1939-08-01), Bruson
patent: 3875215 (1975-04-01), Strycker
patent: WO 93/02040 (1993-02-01), None
Database CAPLUS on STN, Acc. No. 1976:79595, GB 1283892 (abstract).*
Database CAPLUS on STN, Acc. No. 1966:75172, US 3236730 (abstract).*
Database CAPLUS on STN, Acc. No. 1963:448161, Bekhli et al., Meditsinskaya Promyshlennost SSSR (1962), 16(12), p. 7-11 (abstract).*
Houben-weyl, Methoden der Organischen Chemie, Georg Thieme Verlan Stuttgard, Band XI, (1958) pp. 592-599.
Journal of the American College of Toxicology, “Final Report on the Safety Assessment of Benzethonium Chloride and Methylbenzethonium” vol. 4, No. 5, 1985, Mary Ann Lieber, Inc., Publishers, pp. 65-106.
Stuart Warren, “Workbook for Organic Synthesis: The Disconnection Approach”, John Wiley & Sons, 1982, pp. 49-51.
Aigner Rudolf
Crass Gerhard
Raab Klaus
Clariant GmbH
Davis Brian
Silverman Richard P.
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