Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1999-06-09
2001-04-10
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S628000, C568S637000, C568S638000, C560S131000, C560S138000
Reexamination Certificate
active
06215029
ABSTRACT:
The present invention relates to the preparation of halogenated hydroxydiphenyl compounds of the formula
in which
R
1
and R
2
independently of one another are F, Cl or Br;
R
3
and R
4
independently of one another are hydrogen; or C
1
-C
4
alkyl;
m is 1 to 3; and
n is 1 or 2;
and to the use of these compounds as disinfectants for protecting organic materials from microorganisms.
The preparation of halogenated hydroxydiphenyl compounds, in particular of 2-hydroxy-2′,4,4′-trichlorodiphenyl ether (Triclosan; compound of the formula (3)) is usually carried out by diazotisation and subsequent hydrolysis of 2-amino-2′,4,4′-trichlorodiphenyl ether (TADE; compound of the formula (2)).
However, the yield in this preparation method is unsatisfactory, as various competitive chemical reactions can take place.
The present invention is therefore based on the object of finding an economical process for the preparation of halohydroxydiphenyl compounds, in which the undesired side reactions are suppressed.
The object is achieved according to the invention by a four-stage reaction, in which in the first stage a halogenated benzene compound is acylated, in the second stage the acylated compound is etherified using a halogenated phenol compound, in a third stage the etherified compound is oxidized and in a fourth stage the oxidized compound is hydrolysed, according to the following reaction scheme:
In the above scheme, R
1
, R
2
, R
3
, R
4
, m and n are as indicated in formula (1).
In the first reaction step (acylation reaction), compounds of the formula (5) are prepared. Usually, this reaction is carried out in the presence of a Lewis acid, e.g. aluminium halide, in particular aluminium chloride. The Lewis acid is in this case employed in a 1 to 3, preferably 1.25 to 2, molar amount, based on the halogenated compound of the formula (5). A possible acylating reagent for this reaction is an acyl halide, in particular acetyl chloride.
C
1
-C
4
alkyl is preferably a straight-chain or branched alkyl radical, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.
The Lewis acid and acylating reagent are preferably employed in equimolar amounts. The reaction is carried out in the solvents customary for Friedel-Crafts reactions, e.g. methylene chloride or ethylene chloride. The reaction time for this reaction stage plays a minor part and can vary within a wide range, from, for example, 1 to 18 hours.
In the second reaction stage, the compounds of the formula (7) are prepared. The etherification of the free OH group of the halogenated phenol compound of the formula (6) is usually carried out in alkaline medium using a strong organic or preferably inorganic base, e.g. NaOH or KOH, and in the presence of a copper catalyst and an inert organic solvent, e.g. toluene or a xylene isomer mixture. The reaction times for this reaction step are usually 1 to 24 hours, preferably 2 to 10 hours; the temperature ranges from 80 to 250° C., preferably 100 to 170° C.
In the third reaction stage (oxidation), compounds of the formula (8) are prepared. The oxidation of the acyl compound of the formula (7) to the compound of the formula (8) (Baeyer-Villiger oxidation) can be carried out using various oxidizing agents. Suitable oxidizing agents are, for example:
a mixture of dilute peracetic acid and acetic anhydride in the presence of a catalytic amount of perchloric acid;
m-chloroperbenzoic acid (MCPBA) in water;
diperoxydodecanedioic acid (DPDDA);
a mixture of dilute peracetic acid and acetic anhydride and sulfuric acid;
perbenzoic acid (PBA)
a mixture of sodium borate and trifluoroacetic acid;
a mixture of formic acid, hydrogen peroxide, acetic anhydride, phosphorus pentoxide and acetic acid;
a mixture of acetic acid, hydrogen peroxide, acetic anhydride and phosphorus pentoxide;
a mixture of K
2
S
2
O
8
, sulfuric acid and a 1:1 water/methanol mixture;
a mixture of acetic acid and the potassium salt of monoperoxymaleic acid;
a mixture of trichloromethylene, the potassium salt of monoperoxymaleic acid and sodium hydrogen sulfate;
a mixture of maleic anhydride, acetic anhydride, hydrogen peroxide and trichloromethane;
a mixture of maleic anhydride, a urea-hydrogen peroxide complex and acetic acid;
magnesium monoperphthalate;
a mixture of acetic anhydride, sulfuric acid and H
2
O
2
;
a mixture of dichloroacetic acid and H
2
O
2
.
m-Chloroperbenzoic acid (MCPBA), a mixture of sodium borate and trifluoroacetic acid or a mixture of acetic anhydride and H
2
O
2
is preferably used for the oxidation. If desired, a commercially available wetting agent can additionally be added to the oxidizing agent. The reaction times lie in a wide range and range from about 0.5 to about 15 hours, preferably 1 to 8 hours. The reaction temperature ranges from −20 to about 100° C., preferably from 0 to about 85° C.
The subsequent hydrolysis to give the desired halohydroxydiphenyl ether of the formula (1) proceeds quantitatively in the acidic or alkaline medium.
The process according to the invention preferably relates to the preparation of halohydroxydiphenyl compounds of the formula (1), in which
R
1
and R
2
are Cl.
Particularly preferred compounds of the formula (1) are those in which
m is 2 and
n is 1 or
m and n are 1.
Very particularly preferred compounds of the formula (1) have the formula
in which
R
1
and R
2
are Cl; and
m is 2 and
n is 1;
and in particular the compound of the formula
The acyl compounds formed in the 2nd reaction stage (Ullmann condensation) in some cases are novel compounds. These are the compounds of the formula
in which
R
1
′, R
2
′ and R
3
′ independently of one another are F, Cl or Br; and
R
4
′ and R
5
′ independently of one another are hydrogen; or C
1
-C
5
alkyl.
In particular, novel compounds of the formula
are preferred in which
R
1
′, R
2
′ and R
3
′ independently of one another are F, Cl or Br.
The halogenated hydroxydiphenyl compounds prepared according to the invention are insoluble in water, but soluble in dilute sodium hydroxide and potassium hydroxide solution and in virtually all organic solvents. Owing to these solubility requirements, their applicability for the control of microorganisms, in particular of bacteria, and as disinfectants for protecting organic materials and articles from attack by microorganisms is very versatile. Thus they can be applied to these in diluted or undiluted form, for example, together with wetting or dispersing agents, e.g. as soap or syndet solutions for the disinfection and cleaning of human skin and hands, in dental hygiene compositions and hard articles.
The following examples illustrate the invention without restricting it thereto.
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patent: 4564712 (1986-01-01), Kukertz et al.
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patent: 5012017 (1991-04-01), Orvik et al.
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“The Merk Index, 12thEd.”, (1996), p. 1646, No. 9790.
Atkinson et al., J. Med. Chem., 26(10), pp. 1353-1360 (1983).
Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 3rdEd., pp. 485, 589 and 990 (1985).
Lancaster, 93/94, Entries 5784,0286 and 6150 (1994).
Harris et al, Journal of Medicinal Chemistry, vol. 25, No. 7, pp. 855-858, 1982.
Burckhardt Urs
Di Teodoro Armando
Gronde Uwe
Hölzl Werner
Reinehr Dieter
Ciba Specialty Chemicals Corporation
Mansfield Kevin T.
Padmanabhan Sreeni
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