U.S. patent application number 10/281011 was filed with the patent office on 2003-08-28 for hydroxydiphenyl ether compounds.
Invention is credited to Haap, Wolfgang, Holzl, Werner, Kulkarni, Surendra Umesh, Mahtre, Asawari Bhikaji, Ochs, Dietmar, Puchtler, Karin, Radhakrishna, Arakali Srinivasarao, Sawant, Mangesh Shivram, Schnyder, Marcel.
Application Number | 20030162836 10/281011 |
Document ID | / |
Family ID | 8242838 |
Filed Date | 2003-08-28 |
United States Patent
Application |
20030162836 |
Kind Code |
A1 |
Holzl, Werner ; et
al. |
August 28, 2003 |
Hydroxydiphenyl ether compounds
Abstract
The present invention relates to the use of hydroxydiphenyl
ether compounds as antimicrobially active substances, to certain
new compounds of this type and to processes for the preparation of
these compounds.
Inventors: |
Holzl, Werner;
(Eschentzwiller, FR) ; Haap, Wolfgang;
(Grenzach-Wyhlen, DE) ; Ochs, Dietmar;
(Schopfheim, DE) ; Puchtler, Karin; (Fischingen,
DE) ; Schnyder, Marcel; (Birsfelden, CH) ;
Kulkarni, Surendra Umesh; (Mumbai, IN) ;
Radhakrishna, Arakali Srinivasarao; (Bangalore, IN) ;
Sawant, Mangesh Shivram; (Mumbai, IN) ; Mahtre,
Asawari Bhikaji; (Mumbai, IN) |
Correspondence
Address: |
CIBA SPECIALTY CHEMICALS CORPORATION
PATENT DEPARTMENT
540 WHITE PLAINS RD
P O BOX 2005
TARRYTOWN
NY
10591-9005
US
|
Family ID: |
8242838 |
Appl. No.: |
10/281011 |
Filed: |
October 25, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10281011 |
Oct 25, 2002 |
|
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09573403 |
May 18, 2000 |
|
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Current U.S.
Class: |
514/568 ;
514/718 |
Current CPC
Class: |
C11D 3/48 20130101; C07C
43/295 20130101; A01N 31/16 20130101; A61P 17/00 20180101; A61P
1/02 20180101; C07C 45/46 20130101; C11D 7/3227 20130101; C07C
49/84 20130101; A61P 31/04 20180101; A01N 35/04 20130101; A61K
8/347 20130101; C11D 7/263 20130101; A61K 8/35 20130101; A61Q 11/00
20130101; Y10S 514/881 20130101; A61Q 15/00 20130101; A61Q 19/10
20130101; A61P 17/16 20180101; C07C 45/54 20130101; C07C 45/673
20130101; A61Q 5/02 20130101; C07C 47/575 20130101; Y10S 514/901
20130101; A61Q 17/005 20130101; Y10S 514/88 20130101; C07C 45/46
20130101; C07C 49/84 20130101; C07C 45/54 20130101; C07C 49/84
20130101; C07C 45/673 20130101; C07C 49/84 20130101; C07C 45/673
20130101; C07C 47/575 20130101 |
Class at
Publication: |
514/568 ;
514/718 |
International
Class: |
A61K 031/192; A61K
031/075 |
Foreign Application Data
Date |
Code |
Application Number |
May 20, 1999 |
EP |
99810442.6 |
Claims
What is claimed is:
1. Use of hydroxydiphenyl ether compounds of the following formula
127wherein when OH is in the para position with respect to the
ether linkage R.sub.1 and R.sub.2 are independently of each other
hydrogen, hydroxy, C.sub.1-C.sub.20alkyl,
C.sub.1-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.20alkoxy, phenyl or phenyl-C.sub.1-C.sub.3-alkyl;
R.sub.3 is hydrogen, C.sub.1-C.sub.20alkyl or
C.sub.1-C.sub.20alkoxy; R.sub.4 is hydrogen, C.sub.1-C.sub.20alkyl,
hydroxy substituted C.sub.1-C.sub.20alkyl,
C.sub.5-C.sub.7cycloalkyl, hydroxy, formyl, acetonyl,
C.sub.1-C.sub.6alkylcarbonyl, C.sub.2-C.sub.20alkenyl, carboxy,
carboxyC.sub.1-C.sub.3alkyl,
C.sub.1-C.sub.3alkylcarbonylC.sub.1-C.sub.3alkyl or carboxyallyl;
wherein when OH is in the meta position with respect to the ether
linkage R.sub.2 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy
substituted C.sub.1-C.sub.20alkyl or C.sub.1-C.sub.6alkylcarbonyl;
R.sub.1 and R.sub.3 are independently of each other hydrogen,
C.sub.1-C.sub.6alkylcar- bonyl or C.sub.1-C.sub.20alkyl; R.sub.4 is
hydrogen, C.sub.1-C.sub.20alkyl, hydroxy substituted
C.sub.1-C.sub.20alkyl, C.sub.5-C.sub.7cycloalkyl, hydroxy, formyl,
acetonyl, C.sub.1-C.sub.6alkylcarbonyl, C.sub.2-C.sub.20alkenyl,
carboxy, carboxyC.sub.1-C.sub.3alkyl,
C.sub.1-C.sub.3alkylcarbonylC.sub.1-C.sub.3a- lkyl or carboxyallyl;
wherein when OH is in the ortho position with respect to the ether
linkage R.sub.1 is hydrogen, C.sub.1-C.sub.6alkyl carbonyl or
C.sub.1-C.sub.20alkyl; R.sub.4 is hydrogen, C.sub.1-C.sub.20alkyl,
hydroxy substituted C.sub.1-C.sub.20alkyl,
C.sub.1-C.sub.7cycloalkyl, hydroxy, formyl, acetonyl,
C.sub.1-C.sub.6alkylcarbonyl, C.sub.2-C.sub.20alkenyl, carboxy,
carboxyC.sub.1-C.sub.3alkyl,
C.sub.1-C.sub.3alkylcarbonylC.sub.1-C.sub.3a- lkyl or carboxyallyl;
R.sub.2 and R.sub.3 are independently of each other hydrogen,
C.sub.1-C.sub.6 alkyl carbonyl or C.sub.1-C.sub.20 alkyl; with the
proviso that compounds wherein OH is in the para position with
respect to the ether linkage and R.sub.1 and R.sub.3 are both
hydrogen and R.sub.2 is methoxy or methyl; or a compound wherein OH
is in the para position with respect to the ether linkage R.sub.2
is hydrogen, R.sub.1 is isopropyl and R.sub.3 is methyl are
excluded; as antimicrobial agents.
2. Use of the compounds according to claim 1 wherein in formula (1)
when OH is in the para position with respect to the ether linkage
R.sub.1 and R.sub.2 are independently of each other hydrogen,
C.sub.1-C.sub.20alkyl, C.sub.1-C.sub.6 alkyl carbonyl or
C.sub.1-C.sub.20alkoxy; R.sub.3 is hydrogen, C.sub.1-C.sub.20alkyl
or C.sub.1-C.sub.20alkoxy; R.sub.4 is hydrogen,
C.sub.1-C.sub.20alkyl, hydroxy, formyl, acetonyl, allyl,
carboxymethyl, carboxyallyl, hydroxy substituted
C.sub.1-C.sub.20alkyl or C.sub.1-C.sub.6 alkyl carbonyl; wherein
when OH is in the meta position with respect to the ether linkage
R.sub.2 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy substituted
C.sub.1-C.sub.20alkyl or C.sub.1-C.sub.6 alkyl carbonyl; R.sub.1
and R.sub.3 are independently of each other hydrogen,
C.sub.1-C.sub.6 alkyl carbonyl or C.sub.1-C.sub.20alkyl; R.sub.4 is
hydrogen, C.sub.1-C.sub.20alkyl, hydroxy, formyl, acetonyl, allyl,
carboxymethyl, carboxyallyl, hydroxy substituted
C.sub.1-C.sub.20alkyl or C.sub.1-C.sub.6 alkyl carbonyl; wherein
when OH is in the ortho position with respect to the ether linkage
R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl carbonyl or
C.sub.1-C.sub.20alkyl; R.sub.4 is hydrogen, C.sub.1-C.sub.20alkyl,
hydroxy, formyl, acetonyl, allyl, carboxymethyl, carboxyallyl,
hydroxy substituted C.sub.1-C.sub.20alkyl or C.sub.1-C.sub.6 alkyl
carbonyl; R.sub.2 and R.sub.3 are independently of each other
hydrogen, C.sub.1-C.sub.6 alkyl carbonyl or C.sub.1-C.sub.20alkyl;
with the proviso that compounds wherein OH is in the para position
with respect to the ether linkage and R.sub.1 and R.sub.3 are both
hydrogen and R.sub.2 is methoxy or methyl; or a compound wherein OH
is in the para position with respect to the ether linkage R.sub.2
is hydrogen, R.sub.1 is isopropyl and R.sub.3 is methyl are
excluded.
3. Use of the compounds of formula 128according to claim 1, wherein
R.sub.1 is C.sub.1-C.sub.5alkyl.
4. Use of the compounds of formula 129wherein R.sub.4 is
C.sub.1-C.sub.5alykl.
5. Use of the compounds according to one of claims 1 to 4 for
finishing of undyed and dyed or printed fibre materials.
6. Use of the compounds according to one of claims 1 to 4 for the
antimicrobial treatment of skin, mucous membrane or hair.
7. Use of the compounds according to one of claims 1 to 4 for the
incorporation into and for the antimicrobial finishing of polymeric
materials.
8. Use of the compounds according to one of claims 1 to 4 for the
antimicrobial treatment of hard surfaces.
9. Use of the compounds according to one of claims 1 to 4 for the
antimicrobial treatment of teeth and gums.
10. A personal care composition comprising at least one compound of
formula (1) according to claim 1 and cosmetically tolerable
carriers or auxiliaries.
11. An oral care composition comprising at least one compound of
formula (1) according to claim 1.
12. A detergent composition comprising at least one compound of
formula (1)) according to claim 1.
13. Compounds of formula (1) wherein OH is in the ortho position
with respect to the ether linkage and R.sub.2, R.sub.3 and
R.sub.4are hydrogen and R.sub.1 is C.sub.1-C.sub.20 alkyl.
14. Compounds of formula (1) wherein OH is in the meta position
with respect to the ether linkage and R.sub.2, R.sub.3 and
R.sub.4are hydrogen and R.sub.1 is C.sub.1-C.sub.20 alkyl.
15. Compounds of formula (1) wherein OH is in the para position
with respect to the ether linkage and R.sub.2 and R.sub.4are
hydrogen and R.sub.1 and R.sub.3 are C.sub.1-C.sub.20 alkyl.
16. A process for the preparation of compounds according to one of
claims 13 to 15 comprising reacting a substituted phenol with an
ether substituted halogenphenol in the presence of alkali and a
catalytically active quantity of copper or of a copper compound,
then heating the resulting alkyloxybenzol compound in the presence
of hydrogen halide and acid.
17. Compounds of formula (1) wherein OH is in the ortho position
with respect to the ether linkage and R.sub.1, R.sub.2 and R.sub.3
are hydrogen and R.sub.4 is in the meta position with respect to
the ether linkage and is C.sub.1-C.sub.6 alkyl carbonyl.
18. Compounds of formula (1) wherein OH is in the meta position
with respect to the ether linkage and R.sub.1, R.sub.2 and
R.sub.3are hydrogen and R.sub.4 is in the para position with
respect to the ether linkage and is C.sub.1-C.sub.6alkyl
carbonyl.
19. A process for the preparation of compounds according to claims
17 and 18 which comprises reacting an acyl chloride with a
phenoxyphenol in the presence of activated zinc at a temperature of
between 70.degree. c. to 80.degree. C., then heating the resulting
acyl compound at a temperature of 145.degree. C. to 150.degree. C.
in the presence of aluminium chloride.
20. Compounds of formula (1) wherein OH is in the meta position
with respect to the ether linkage and R.sub.1, R.sub.2 and R.sub.3
are hydrogen and R.sub.4 is in the para position with respect to
the ether linkage and is C.sub.1-C.sub.20alkyl.
21. A process for the preparation of compounds according to claims
17 and 18 which comprises reacting an acyl chloride with a
phenoxyphenol in the presence of activated zinc at a temperature of
between 70.degree. c. to 80.degree. C., then heating the resulting
acyl compound at a temperature of 145.degree. C. to 150.degree. C.
in the presence of aluminium chloride, then refluxing the resulting
acylated phenol in the presence of amalgamated zinc, hydrochloric
acid and a solvent such as toluene.
Description
[0001] The present invention relates to the use of hydroxydiphenyl
ether compounds as antimicrobially active substances, to certain
new compounds of this type and to processes for the preparation of
these compounds.
[0002] It is known that certain halogenated diphenyl ether
compounds have an excellent antimicrobial activity. These compounds
are therefore widely used, for example as active substances for the
antimicrobial finishing of medical items and household articles, as
detergent additive and in the hygiene sector, for example in soaps
or dental hygiene products. Such halogenated compounds are
described in DE 2538016. However it is desirable to be able to
provide non-halogenated agents which are highly effective
antimicrobial agents. Polymeric materials can be antimicrobially
finished by incorporating halogenated diphenyl ether compounds, the
active substances being, as a result of their excellent migration
properties, constantly conveyed to the surface of the corresponding
material ("slow release"). For certain industrial applications,
this effect is undesired since the long-term effect of
antimicrobially finished materials such as textiles, paper,
plastics, cellulose sponges etc. is reduced at the same time.
[0003] The object of the present invention is thus to provide
non-halogenated hydroxydiphenyl ether compounds for use as
antimicrobially active substances and which, at the same time, are
stable to migration.
[0004] The present invention provides the use of hydroxydiphenyl
ether compounds of the following formula 1
[0005] wherein when OH is in the para position with respect to the
ether linkage
[0006] R.sub.1 and R.sub.2 are independently of each other
hydrogen, hydroxy, C.sub.1-C.sub.20alkyl,
C.sub.1-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkylcarbonyl,
C.sub.1-C.sub.20alkoxy, phenyl or phenyl-C.sub.1-C.sub.3-alkyl;
[0007] R.sub.3 is hydrogen, C.sub.1-C.sub.20alkyl or
C.sub.1-C.sub.20alkoxy;
[0008] R.sub.4 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy
substituted C.sub.1-C.sub.20alkyl, C.sub.5-C.sub.7cycloalkyl,
hydroxy, formyl, acetonyl, C.sub.1-C.sub.6alkylcarbonyl,
C.sub.2-C.sub.20alkenyl, carboxy, carboxyC.sub.1-C.sub.3alkyl,
C.sub.1-C.sub.3alkylcarbonylC.sub.1-C.sub.3a- lkyl or
carboxyallyl;
[0009] wherein when OH is in the meta position with respect to the
ether linkage
[0010] R.sub.2 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy
substituted C.sub.1-C.sub.20alkyl or
C.sub.1-C.sub.6alkylcarbonyl;
[0011] R.sub.1 and R.sub.3 are independently of each other
hydrogen, C.sub.1-C.sub.6alkylcarbonyl or
C.sub.1-C.sub.20alkyl;
[0012] R.sub.4 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy
substituted C.sub.1-C.sub.20alkyl, C.sub.1-C.sub.7cycloalkyl,
hydroxy, formyl, acetonyl, C.sub.1-C.sub.6alkylcarbonyl,
C.sub.2-C.sub.20alkenyl, carboxy, carboxyC.sub.1-C.sub.3alkyl,
C.sub.1-C.sub.3alkylcarbonylC.sub.1-C.sub.3a- lkyl or
carboxyallyl;
[0013] wherein when OH is in the ortho position with respect to the
ether linkage
[0014] R.sub.1 is hydrogen, C.sub.1-C.sub.6alkyl carbonyl or
C.sub.1-C.sub.20alkyl;
[0015] R.sub.4 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy
substituted C.sub.1-C.sub.20alkyl, C.sub.5-C.sub.7cycloalkyl,
hydroxy, formyl, acetonyl, C.sub.1-C.sub.6alkylcarbonyl,
C.sub.2-C.sub.20alkenyl, carboxy, carboxyC.sub.1-C.sub.3alkyl,
C.sub.1-C.sub.3alkylcarbonylC.sub.1-C.sub.3a- lkyl or
carboxyallyl;
[0016] R.sub.2 and R.sub.3 are independently of each other
hydrogen, C.sub.1-C.sub.6 alkyl carbonyl or
C.sub.1-C.sub.20alkyl;
[0017] with the proviso that compounds wherein OH is in the para
position with respect to the ether linkage and R.sub.1 and R.sub.3
are both hydrogen and R.sub.2 is methoxy or methyl; or a compound
wherein OH is in the para position with respect to the ether
linkage R.sub.2 is hydrogen, R.sub.1 is isopropyl and R.sub.3 is
methyl are excluded; as antimicrobial agents.
[0018] C.sub.1-C.sub.20alkyl is straight-chain or branched alkyl
radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, tert-butyl, pentyl, iso-pentyl, tert-pentyl, hexyl,
cyclohexyl, heptyl, octyl, isooctyl, nonyl or decyl and the
like.
[0019] C.sub.1-C.sub.20alkoxy is straight-chain or branched alkoxy
radicals such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
sec-butoxy, tert-butoxy, pentyloxy, iso-pentyloxy, tert-pentyloxy,
heptyloxy, octyloxy, isooctyloxy, nonyloxy or decyloxy and the
like.
[0020] C.sub.1-C.sub.6alkyl carbonyl is straight-chain or branched
carbonyl radicals such as acetyl, propionyl, butyryl, isobutyryl,
valeryl, isovaleryl or pivaloyl and the like.
[0021] Hydroxy substituted C.sub.1-C.sub.20alkyl is hydroxymethyl,
hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl,
hydroxyhexyl, hydroxyheptyl, hydroxyoctyl, hydroxynonyl or
hydroxydecyl and the like.
[0022] Preferably compounds of formula (1) are used wherein, when
OH is in the para position with respect to the ether linkage
[0023] R.sub.1 and R.sub.2 are independently of each other
hydrogen, C.sub.1-C.sub.20alkyl, C.sub.1-C.sub.6 alkyl carbonyl or
C.sub.1-C.sub.20alkoxy;
[0024] R.sub.3 is hydrogen, C.sub.1-C.sub.10alkyl or
C.sub.1-C.sub.20alkoxy;
[0025] R.sub.4 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy, formyl,
acetonyl, allyl, carboxymethyl, carboxyallyl, hydroxy substituted
C.sub.1-C.sub.20alkyl or C.sub.1-C.sub.6 alkyl carbonyl;
[0026] wherein when OH is in the meta position with respect to the
ether linkage
[0027] R.sub.2 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy
substituted C.sub.1-C.sub.20alkyl or C.sub.1-C.sub.6alkyl
carbonyl;
[0028] R.sub.1 and R.sub.3 are independently of each other
hydrogen, C.sub.1-C.sub.6alkyl carbonyl or
C.sub.1-C.sub.20alkyl;
[0029] R.sub.4 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy, formyl,
acetonyl, allyl, carboxymethyl, carboxyallyl, hydroxy substituted
C.sub.1-C.sub.20alkyl or C.sub.1-C.sub.6 alkyl carbonyl;
[0030] wherein when OH is in the ortho position with respect to the
ether linkage
[0031] R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl carbonyl or
C.sub.1-C.sub.20alkyl;
[0032] R.sub.4 is hydrogen, C.sub.1-C.sub.20alkyl, hydroxy, formyl,
acetonyl, allyl, carboxymethyl, carboxyallyl, hydroxy substituted
C.sub.1-C.sub.20alkyl or C.sub.1-C.sub.6 alkyl carbonyl;
[0033] R.sub.2 and R.sub.3 are independently of each other
hydrogen, C.sub.1-C.sub.6 alkyl carbonyl or C.sub.1-C.sub.20alkyl;
with the proviso that compounds wherein OH is in the para position
with respect to the ether linkage and R.sub.1 and R.sub.3 are both
hydrogen and R.sub.2 is methoxy or methyl; or a compound wherein OH
is in the para position with respect to the ether linkage R.sub.2
is hydrogen, R.sub.1 is isopropyl and R.sub.3 is methyl are
excluded.
[0034] Another aspect of the invention are certain compounds
described by formula (1) which are novel.
[0035] These novel compounds are of formula (1) wherein when OH is
in the ortho position with respect to the ether linkage and
R.sub.2, R.sub.3 and R.sub.4 are hydrogen and R.sub.1 is
C.sub.1-C.sub.20alkyl.
[0036] Preferably these novel compounds are of formula (1) wherein
when OH is in the ortho position with respect to the ether linkage
and R.sub.2, R.sub.3 and R.sub.4are hydrogen and R.sub.1 is
C.sub.1-C.sub.5alkyl.
[0037] Compounds of particular interest include the following:
2
[0038] Further novel compounds are of formula (1) wherein when OH
is in the meta position with respect to the ether linkage and
R.sub.2, R.sub.3 and R.sub.4are hydrogen and R.sub.1 is
C.sub.1-C.sub.20alkyl.
[0039] Preferably these novel compounds are of formula (1) wherein
when OH is in the meta position with respect to the ether linkage
and R.sub.2, R.sub.3 and R.sub.4 are hydrogen and R.sub.1 is
C.sub.1-C.sub.5 alkyl.
[0040] Compounds of particular interest include the following:
3
[0041] wherein
[0042] R.sub.1 is C.sub.1-C.sub.5alkyl; for example the compound of
formula 4
[0043] or compounds of formula 5
[0044] wherein
[0045] R.sub.4 is C.sub.1-C.sub.5alykl, for example the compound of
formula 6
[0046] Further novel compounds are of formula (1) wherein when OH
is in the para position with respect to the ether linkage and
R.sub.2 and R.sub.4 are hydrogen and R.sub.1 and R.sub.3 are
C.sub.1-C.sub.20alkyl.
[0047] Preferably these novel compounds are of formula (1) wherein
when OH is in the meta position with respect to the ether linkage
and R.sub.2 and R.sub.4 are hydrogen and R.sub.1 and R.sub.3 are
C.sub.1-C.sub.5 alkyl.
[0048] Compounds of particular interest include the following:
7
[0049] Another aspect of the present invention is a process for the
preparation of compounds of formula (1) wherein when OH is in the
ortho position with respect to the ether linkage and R.sub.2,
R.sub.3 and R.sub.4 are hydrogen and R.sub.1 is
C.sub.1-C.sub.20alkyl, compounds of formula (1) wherein when OH is
in the meta position with respect to the ether linkage and R.sub.2,
R.sub.3 and R.sub.4are hydrogen and R.sub.1 is
C.sub.1-C.sub.20alkyl and compounds of formula (1) wherein when OH
is in the para position with respect to the ether linkage and
R.sub.2 and R.sub.4are hydrogen and R.sub.1 and R.sub.3 are
C.sub.1-C.sub.20alkyl.
[0050] The process comprises reacting a susbstituted phenol with an
ether substituted halogenphenol in the presence of alkali and a
catalytically active quantity of copper or of a copper compound,
and the resulting alkyloxybenzol compound is then heated in the
presence of hydrogen halide and acid in order to convert the
alkyloxy group to a hydroxy group. An example of the reaction
scheme is shown below, wherein R represents one of the groups
R.sub.1, R.sub.2 or R.sub.3. 8
[0051] Preferred combinations of reagents include
2-C.sub.1-C.sub.20alkyl substituted phenols and
2-methoxy-bromophenol.
[0052] Other preferred combinations of reagents include
2-C.sub.1-C.sub.20alkyl substituted phenols and
3-methoxy-bromophenol.
[0053] Other preferred combinations of reagents include
2,5-C.sub.1-C.sub.20dialkyl substituted phenols and
4-methoxy-bromophenol. Preferred bases are hydroxides/carbonates
from group 1/2 metals.
[0054] The alkali required for the reaction can be added in
different forms. For example the substituted phenol can be reacted
in the form of alkali phenolate. It is also possible to introduce
for example solid potassium hydrate into the mixture of phenol and
halogenphenol, in which case homogeneity can be achieved by heating
to 120 to 130.degree. C. It is also possible to use aqueous alkali
solutions and remove the water during the reaction, for example by
azeotropic distillation in the presence of an organic entrailing
agent.
[0055] The reaction may be also carried out in the presence of a
solvent such as an aliphatic ether containing 6 or more carbon
atoms and boiling at a temperature above 130.degree. C. and also
ethers of polyglycols such as di- and tri-ethylene gylcol and in
high boiling solvents as Pyridin, DMF, DMA, DMSO, Toluene, Xylene
etc.
[0056] General catalysts for Ullmann condensation are Cu,
Cu.sub.2Cl.sub.2, bas. CuCO.sub.3/CuCl.sub.2, CuO or Cu.sub.2O.
Copper or copper compounds are used in known manner as catalysts
for example in quantities of from 0.1 to 2.5% based on the
halogenphenol. The reaction temperatures are generally from
150.degree. C. to 200.degree. C. whilst the reaction times vary
from 1 to 16 hours. The reaction may be carried out under elevated
pressure.
[0057] Suitable reagents used in the demethylation step include
hydrogen bromide. Suitable acids used in the demethylation step
include acetic acid. General reagents are AlCl.sub.3, BCl.sub.3,
BF.sub.3, HBr, Hl, preferably pyridinium.times.HCl.
[0058] The reaction can be worked up in the usual way. Unreacted
starting materials can be separated off by distillation, optionally
under vacuum.
[0059] A further aspect of the invention includes other certain
compounds described by formula (1) which are novel.
[0060] These novel compounds are of formula (1) wherein when OH is
in the ortho position with respect to the ether linkage
[0061] R.sub.1, R.sub.2 and R.sub.3are hydrogen;
[0062] R.sub.4 is in the meta position with respect to the ether
linkage and is C.sub.1-C.sub.6 alkyl carbonyl.
[0063] Compounds of particular interest include the following:
9
[0064] further novel compounds are of formula (1) wherein when OH
is in the meta position with respect to the ether linkage and
R.sub.1, R.sub.2 and R.sub.3 are hydrogen and R.sub.4 is in the
para position with respect to the ether linkage and is
C.sub.1-C.sub.6 alkyl carbonyl.
[0065] Compounds of particular interest include the following:
10
[0066] A further aspect of the present invention is another process
for the preparation of compounds of formula (1) wherein when OH is
in the meta position with respect to the ether linkage and R.sub.1,
R.sub.2 and R.sub.3 are hydrogen and R.sub.4 is in the para
position with respect to the ether linkage and is C.sub.1-C.sub.6
alkyl carbonyl and also for compounds of formula (1) wherein when
OH is in the ortho position with respect to the ether linkage and
R.sub.1, R.sub.2 and R.sub.3are hydrogen and R.sub.4 is in the meta
position with respect to the ether linkage and is C.sub.1-C.sub.6
alkyl carbonyl.
[0067] The process comprises reacting an acyl chloride with a
phenoxyphenol, such as meta-phenoxyphenol or ortho-phenoxyphenol,
in the presence of activated zinc at a temperature of between
70.degree. c. to 80.degree. C. The hydroxyl group undergoes
acylation, as shown in the scheme below: 11
[0068] This acyl compound then undergoes a "Fries rearrangement" in
the presence of aluminium chloride at a temperature of 145.degree.
C. to 150.degree. C., producing an acylated phenol. 12
[0069] Preferably R.sub.6 is C.sub.1-C.sub.6alkylcarbonyl.
[0070] These compounds may also be amenable by direct acylation of
phenols with catalysts such as Lewis acids as AlCl.sub.3,
ZnCl.sub.2, FeCl.sub.3, BCl.sub.3, BF.sub.3, transition metal
trifluorosulfonates (eg. Sc(OTf).sub.3) in inert solvents as EDC,
CH.sub.2Cl.sub.2, CS.sub.2 or nitrobenzene.
[0071] Further novel compounds are of formula (1) wherein when OH
is in the meta position with respect to the ether linkage and
R.sub.1, R.sub.2 and R.sub.3are hydrogen and R.sub.4 is in the para
position with respect to the ether linkage and is
C.sub.1-C.sub.20alkyl.
[0072] Preferably these novel compounds are of formula (1) wherein
when OH is in the meta position with respect to the ether
linkage
[0073] R.sub.1, R.sub.2 and R.sub.3are hydrogen;
[0074] R.sub.4 is in the para position with respect to the ether
linkage and is C.sub.1-C.sub.5alkyl.
[0075] Compounds of particular interest include the following:
13
[0076] A further aspect of the present invention is another process
for the preparation of compounds of formula (1) wherein when OH is
in the meta position with respect to the ether linkage and R.sub.1,
R.sub.2 and R.sub.3are hydrogen and R.sub.4 is in the para position
with respect to the ether linkage and is C.sub.1-C.sub.20alkyl.
[0077] The process comprises reacting an acyl chloride with
meta-phenoxyphenol in the presence of activated zinc at a
temperature of between 70.degree. c. to 80.degree. C. The hydroxyl
group undergoes acylation, as shown in the scheme below: 14
[0078] This acyl compound then undergoes a "Fries rearrangement" in
the presence of aluminium chloride at a temperature of 145.degree.
C. to 150.degree. C., producing an acylated phenol. 15
[0079] This acylated phenol is then refluxed in the presence of
amalgamated zinc, hydrochloric acid and a solvent such as toluene,
to yield the end product. 16
[0080] R.sub.6 is C.sub.1-C.sub.19alkyl.
[0081] Reduction to these compounds is also achieved by catalytic
hydrogenation.
[0082] Alternatively, compounds of formula (1) wherein the hydroxy
group is in para position with respect to the ether linkage can be
obtained by the "benzylic ether route" according to the following
reaction scheme: 17
[0083] This is basically the same synthesis route as described
above but it's applying the benzylic ether of p-bromo phenol
instead of the methyl ether.
[0084] The following ether compounds can also be employed: 18
[0085] The hydroxydiphenyl ether compounds according to the
invention are thermally stable and antimicrobially effective
compounds of low volatility and having a severely reduced tendency
to migrate. They are therefore suitable for the antimicrobial
finishing of polymeric compounds, for example in plastics, rubbers,
paints, surface coatings, (textile) fibres which are exposed to a
microbially contaminated environment.
[0086] Examples of polymers and other substrates which can be
antimicrobially finished in this way are:
[0087] polymers of mono- and diolefins,
[0088] polyolefins,
[0089] copolymers of mono- and diolefins with one another or with
other vinyl monomers,
[0090] hydrocarbon resins,
[0091] polystyrene,
[0092] copolymers of styrene or .alpha.-methylstyrene or dienes or
acrylic derivatives,
[0093] graft copolymers of styrene or .alpha.-methylstyrene.
[0094] halogen-containing polymers,
[0095] polymers derived from .alpha.,.beta.-unsaturated acids and
derivatives thereof, such as polyacrylates and
polymethacrylates,
[0096] polymers derived from unsaturated alcohols and amines or
acyl derivatives or acetals thereof,
[0097] homo- and copolymers of cyclic ethers, polyacetals,
polyphenylene oxides and polyphenylene sulfides and mixtures
thereof with styrene polymers or polyamides,
[0098] polyurethanes derived from polyethers, polyesters and
polybutadienes having terminal hydroxyl groups on the one hand and
aliphatic or aromatic polyisocyanates on the other, and precursors
thereof,
[0099] polyamides and copolyamides derived from diamines and
dicarboxylic acids and/or from aminocarboxylic acids or the
corresponding lactams,
[0100] polyureas, polyimides, polyamide-imides, polyetherimides,
polyesterimides, polyhydantoins and polybenzimidazoles,
[0101] polyesters,
[0102] polycarbonates and polyester carbonates,
[0103] polysulfones, polyether sulfones and polyether ketones,
[0104] crosslinked polymers derived from aldehydes on the one hand
and phenols, urea or melamine on the other hand, such as
phenol-formaldehyde resins, urea-formaldehyde resins and
melamine-formaldehyde resins,
[0105] drying and non-drying alkyd resins,
[0106] unsaturated polyester resins,
[0107] crosslinkable acrylic resins,
[0108] alkyd resins, polyester resins and acrylate resins,
[0109] crosslinked epoxy resins,
[0110] superabsorbent polymers
[0111] natural polymers, such as cellulose, natural rubber,
gelatine, and derivatives thereof modified chemically in a
polymer-homologous manner, such as cellulose acetates, cellulose
propionates cellulose butyrates, or the cellulose ethers, such as
methylcellulose; and also rosins and derivatives.
[0112] The invention thus also provides a composition
comprising
[0113] (A) an organic material to be antimicrobially finished
and
[0114] (B) a compound of the formula (1).
[0115] The invention also relates to a process for the
antimicrobial finishing of an organic material, which comprises
adding at least one compound of the formula (1) thereto, and to the
use of the compound of the formula (1) for the antimicrobial
finishing of polymeric materials.
[0116] The amount of antimicrobial active substance to be used
depends on the organic material to be antimicrobially finished and
on the intended use of the material finished in this way. The
composition according to the invention generally comprises, per 100
parts by weight of component (A), from 0.01 to 15 parts by weight,
in particular from 0.05 to 10 parts by weight, and especially from
0.1 to 5 parts by weight of the antimicrobial active substance
(component (B)).
[0117] The antimicrobial active substance (component (B)) can also
be a mixture of two or more compounds of the formula (1). The
compositions according to the invention can, in addition to the
compounds according to the invention, also comprise other
additives, for example antioxidants or light protection agents.
[0118] Incorporation into the organic polymers, for example into
the synthetic organic, in particular thermoplastic, polymers can
take place by adding the hydroxydiphenyl ether compound according
to the invention and, if desired, other additives by the methods
customary in the art. Incorporation can expediently take place
before or during shaping, for example by mixing the pulverulent
components or by adding the antimicrobial active substance to the
melt or solution of the polymer, or by applying the dissolved or
dispersed compounds to the polymer, if desired with subsequent
evaporation of the solvent. Another method of incorporating the
mixtures according to the invention into polymers involves adding
the former before or during polymerization of the corresponding
monomers or before crosslinking.
[0119] The mixtures according to the invention can also be added to
the organic polymers to be finished in the form of a masterbatch
which comprises these compounds, for example, in a concentration of
from 2.5 to 25% by weight.
[0120] The resulting antimicrobially finished polymer compositions
can be converted into shaped articles, for example fibres, films,
tapes, sheets, multi-wall sheets, containers, tubes and other
profiles, by conventional methods, for example by hot pressing,
spinning, extrusion or injection moulding.
[0121] The hydroxydiphenyl ether compounds of the formula (1) are
also suitable for the antimicrobial finishing of undyed and dyed or
printed fibre materials made, for example, of silk, wool,
polyamide, polyester or polyurethane, and in particular of
cellulosic fibre materials of all types. Examples of such fibre
materials are the natural cellulose fibres, such as cotton, linen,
jute and hemp, and also pulp and regenerated cellulose. The
hydroxydiphenyl ether compounds according to the invention are also
suitable for the antimicrobial finishing of
hydroxyl-group-containing fibres which are present in mixed
fabrics, for example, of mixtures of cotton with polyester fibres
or polyamide fibres. The hydroxydiphenyl ether compounds of the
formula (1) are also suitable for incorporation into
non-wovens.
[0122] "Non-woven" is a type of fabric that is not spun and woven
into a cloth, but instead bonded together. According to the ISO
definition it is a manufactured sheet, web, or batt of
directionally or randomly orientated fibres, bonded by friction,
and/or adhesion.
[0123] Nonwoven textiles are widely used in disposable as well as
durable goods, such as baby diaper, feminine hygiene, adult
incontinence, wipers, bed linings, automotive industries, medical
face masks, air and water filtration, home furnishing and
geotextiles. Such materials can be fabricated by different
techniques, such as spunbonding, melt blown, carded thermal bonding
and carded chemical bonding, dry and/or wet laid and needlefelts.
Because of the nature of such applications, increasingly the market
is demanding products with specific properties such as
antimicrobial efficacy.
[0124] For this purpose, one or more compounds of the formula (1)
are advantageously applied to the textile fibre material in an
amount of from 0.01 to 20% by weight, preferably 0.1-3% by weight,
and in particular from 0.25 to 2% by weight, based on the weight of
the fibre material, in a process analogous to dyeing.
[0125] The hydroxydiphenyl ether compounds according to the
invention can be applied to the fibre material and fixed to the
fibre in different ways, in particular in the form of aqueous
dispersions or printing pastes.
[0126] The textile fibre materials finished using the compounds of
the formula (1) according to the invention have an excellent and
long-lasting antimicrobial protection.
[0127] An antimicrobial textile treatment formulation has, for
example, the following composition:
[0128] 20% by weight of a compound of formula (1)
[0129] 5% by weight of sodium lauryl sulfate
[0130] 10% by weight of an ethoxylated fatty alcohol
[0131] 40% by weight of propylene glycol and
[0132] 25% by weight of water.
[0133] The hydroxydiphenyl ether compounds according to the
invention can be also be used in paper finishing, printing
thickeners containing starch, varnishes and paints.
[0134] The hydroxydiphenyl ether compounds according to the
invention are also useful for the disinfection and general
antimicrobial treatment, such as deodorising, of the skin, mucous
membrane and hair, preferably for the disinfection of hands and
wounds. The hydroxydiphenyl ether compounds according to the
invention are useful for the preservation of cosmetic and household
products against microbial spoilage.
[0135] Therefore, these compounds are suitable as an antimicrobial
active substance in personal care products as shampoos, bath- and
shower additives, hair-care products, liquid and bar soaps, lotions
and cremes, deodorants, other aqueous or alcoholic solutions, for
example cleaning solutions for the skin, moist cleaning sheets,
oils and powders.
[0136] A further subject of the present invention is therefore a
personal care composition comprising at least one compound of the
formula (1) and cosmetically tolerable carriers or auxiliaries.
[0137] The personal care composition according to the present
invention comprises 0.01 to 15, preferably 0.5 to 10% b.w. of the
hydroxydiphenyl ether compounds of formula (1) and cosmetically
tolerable carriers or auxiliaries.
[0138] The personal care composition according to the invention can
be formulated as a water-in-oil or oil-in-water emulsion, as an
oil-in-alcohol lotion, as a vesicular dispersion of an ionic or
non-ionic amphiphilic lipid, as a gel, solid stick, aerosol
formulation or a surfactant based formulation, such as a soap or
skin cleanser.
[0139] As a water-in-oil or oil-in-water emulsion, the cosmetically
compatible auxiliary preferably contains 5 to 50% of an oil phase,
5 to 20% of an emulsifier and 30 to 90% of water. The oil phase can
in this case contain any oil suitable for cosmetic formulations,
e.g. one or more hydrocarbon oils, a wax, a natural oil, a silicone
oil, a fatty acid ester or a fatty alcohol. Preferred mono- or
polyols are ethanol, isopropanol, propylene glycol, hexylene
glycol, glycerol and sorbitol.
[0140] Any conventionally usable emulsifier can be used for the
cosmetic composition according to the invention, for example one or
more ethoxylated esters of natural derivatives, e.g.
poly-ethoxylated esters of hydrogenated castor oil; or a silicone
oil emulsifier, e.g. a silicone polyol; an optionally ethoxylated
fatty acid soap; an ethoxylated fatty alcohol; an optionally
ethoxylated sorbitan ester; an ethoxylated fatty acid; or an
ethoxylated glyceride.
[0141] The cosmetic composition may also comprise further
components, e.g. emollients, emulsion stabilisers, skin humectants,
skin tanning accelerators, thickeners, such as xanthan,
moisture-retention agents, such as glycerol, preservatives,
perfumes and colourings.
[0142] The preparation of the cosmetic composition can be effected
by physically mixing the antimicrobial(s) with the auxiliary by
customary methods, for example by simply stirring the individual
components together.
[0143] Cosmetic formulations include a very wide range of cosmetic
products. Suitable products are, for example, especially the
following:
[0144] skin-care products, for example skin washing and cleansing
products in the form of bars of soap or liquid soaps, syndets or
washing pastes,
[0145] bath products, for example liquid (foam baths, milks, shower
products) or solid bath products, such as bath pearls and bath
salts;
[0146] skin-care products, such as skin emulsions, multiple
emulsions or skin oils;
[0147] decorative body-care products, for example face make-ups in
the form of day or powder creams, face powders (lose and
compressed), rouge or cream make-ups, eye-care products, for
example eye shadow products, mascara, eyeliners, eye creams or
eye-fix creams; lip-care products, for example lipstick, lip gloss,
lip liner, nail-care products, such as nail varnish, nail varnish
remover, nail hardeners or cuticle removers;
[0148] feminine hygiene products, such as feminine hygiene washing
lotions or sprays;
[0149] foot-care products, for example foot baths, foot powders,
food creams or foot balms, special deodorants and antiperspirants
or products for scrubbing off callouses;
[0150] sunscreens, such as sun milks, lotions, creams, oils,
sunblockers or tropicals, pre-sun products or after-sun
products;
[0151] suntanning products, for example self-tanning creams;
[0152] depigmenting products, for example products for bleaching or
lightening skin;
[0153] insect repellents, for example insect oils, lotions, sprays
or sticks;
[0154] deodorants, for example deodorant sprays, non-aerosol
sprays, deodorant gels, sticks or roll-ons;
[0155] antiperspirants, for example antiperspirant sticks, creams
or roll-ons;
[0156] products for cleansing and treating impure skin, for example
syndets (solid or liquid), peeling or scrubbing products or peeling
masks;
[0157] chemical depilatory products, for example depilatory
powders, liquid depilatory products, creamy or pasty depilatory
products, depilatory gels or aerosol foams;
[0158] shaving products, for example shaving soap, foaming shaving
creams, non-foaming shaving creams, shaving foams and gels,
preshaving products for dry shaving, aftershaves or aftershave
lotions;
[0159] scents, for example perfumes (Eau de Cologne, Eau de
Toilette, Eau de Parfum, Parfum de Toilette, perfume), perfume oils
or perfume creams;
[0160] products for oral and dental hygiene as well as for
dentures, for example toothpastes, tooth gels, tooth powders,
mouth-wash concentrates, anti-plaque mouth-washes, denture cleaning
products or denture adhesion products;
[0161] cosmetic formulations for hair treatment, for example hair
washes in the form of shampoos, hair conditioners, hair-care
products, for example pretreatment products, hair tonics, hair
styling creams and gels, pomades, hair rinses, deep conditioning
treatments, intensive hair care treatments, hair setting products,
for example waving agents for perms (hot wave, mild wave, cold
wave), hair straightening products, liquid hair fixatives, hair
foams, hair sprays, bleaching agents, for example hydrogen peroxide
solutions, bleaching shampoos, bleaching creams, bleaching powders,
bleaching pastes or oils, temporary, semitemporary or permanent
hair dyes, products containing self-oxidising dyes, or natural hair
dyes, such as henna or camomile.
[0162] An antimicrobial soap has, for example, the following
composition:
[0163] 0.01 to 5% by weight of a compound of the formula (1)
[0164] 0.3 to 1% by weight of titanium dioxide
[0165] 1 to 10% by weight of stearic acid
[0166] to 100% of soap base, for example the sodium salts of tallow
fatty and coconut fatty acid or glycerols.
[0167] A shampoo has, for example, the following composition:
[0168] 0.01 to 5% by weight of a compound of the formula (1)
[0169] 12.0% by weight of sodium laureth-2-sulfate,
[0170] 4.0% by weight of cocamidopropylbetaine,
[0171] 3.0% by weight of NaCl and
[0172] water to 100%.
[0173] A deodorant has, for example, the following composition:
[0174] 0.01 to 5% by weight of a compound of the formula (1)
[0175] 60% by weight of ethanol,
[0176] 0.3% by weight of perfume oil and
[0177] water to 100%.
[0178] The personal care formulations listed above can be in a very
wide range of forms of presentation, for example
[0179] in the form of liquid formulations as an O/W emulsion,
[0180] in the form of a gel,
[0181] in the form of an oil, cream, milk or lotion,
[0182] in the form of a powder, lacquer, pellets or make-up,
[0183] in the form of a stick,
[0184] in the form of a spray (spray with propellant or pumping
spray) or an aerosol,
[0185] in the form of a foam, or
[0186] in the form of a paste.
[0187] The oral hygiene composition may comprise an additional
antibacterial enhancing agent, for example an anionic polymeric
polycarboxylate, a dehydrated polyphosphate salt, a compound which
provides a source of fluoride ions, a polishing material, including
siliceous material or sodium bicarbonate, an orally acceptable
vehicle, including a water-phase with humectant, thickeners,
surface-active agents and a flavoring or sweetening material.
[0188] The oral hygiene composition according to the invention
contains from 0.003 to 5% by weight based on the total weight of
the composition, of antimicrobial or a mixture of
antimicrobials.
[0189] The preparation of the oral hygiene composition can be
effected by physically mixing the antimicrobial(s) with the other
ingredients by customary methods, for example by simply stirring
the individual components together, then mixing further under
vacuum.
[0190] An oral care formulation has, for example, the following
composition:
[0191] 10% by weight of Sorbitol,
[0192] 10% by weight of Glycerin,
[0193] 15% by weight of Ethanol,
[0194] 15% by weight of Propylene gylcol,
[0195] 0.5% by weight of Sodium lauryl sulfate,
[0196] 0.25% by weight of Sodium methyl cocyl taurate,
[0197] 0.25% by weight of Poloxypropylene/polyoxyethylene block
copolymer,
[0198] 0.10% by weight of Mint flavor,
[0199] 0.3% by weight of a compound of formula (1),
[0200] 48.6% by weight of water.
[0201] The oral hygiene composition may be in various forms of
presentation including the form of a gel, paste, cream or
mouthwash.
[0202] Furthermore the hydroxydiphenyl ether compounds according to
the invention are useful as household cleaners for the cleaning and
disinfection of hard surfaces.
[0203] A detergent has, for example, the following composition:
[0204] 0.01 to 5% by weight of a compound of the formula (1)
[0205] 3.0% by weight of Octanol 4EO,
[0206] 1.3% by weight Fatty alcohol C.sub.8-C.sub.10
Polyglucoside,
[0207] 3.0% by weight Isopropanol,
[0208] water to 100%.
[0209] A better understanding of the present invention and of its
many advantages will be had by referring to the following Examples,
given by way of illustration.
EXAMPLE 1
[0210] 19
[0211] The mixture of 6.1 g (0.05 mol) 2,5-Dimethylphenol, 2.8 g
(0.05 mol) KOH, 0.4 g (0.006 mol) copper powder and 50 g (0.25 mol)
bromo anisole is heated in a standard reaction apparatus, equipped
with a water trap, to 160.degree. C. for 5 h. After cooling the
reaction mass is suspended in toluene and filtrated. After
distilling off the solvent and excess reagent the product of
formula (101a) is isolated by distillation at 125.degree. C./0.01
mbar. A colourless oil is obtained, slowly crystallizing at room
temperature. Yield: 4.6 g (40%) 20
[0212] 4.6 g (0.02 mol) of 4-(2,5-Dimethylphenoxy)-methoxybenzol
and 30 ml HBr (47% solution in water) are heated to reflux in 100
ml acetic acid for 4 h. After cooling and distilling off acetic
acid the reaction mass is dissolved in 100 ml methylene chloride
and washed with 200 ml water with pH adjusted to pH 10 with 10%
NaOH. Product of formula (101) is isolated from the organic phase
by distillation at 160.degree. C./0.01 mbar. Yield: 2.2 g (52%)
EXAMPLE 2
[0213] 21
[0214] Into a three necked flask equipped with overhead stirrer
& condenser was charged Acid chloride [57.25 m.moles], Toluene
[250 ml] & activated zinc [57.24 m.moles]. This mixture stirred
at room temperature [30.degree. C.], for 15 minutes.
m-Phenoxyphenol [4.5 g. 24.20 m.moles] in Toluene [150 ml], was
added and the reaction mixture stirred at 70-75.degree. C. for 30
minutes. TLC showed the absence of starting material. Reaction
mixture cooled to room temperature & filtered. Organic layer
washed with 2.times.100 ml of aqueous solution [20%] of Potassium
carbonate followed by water wash. It was briefly drided over
anhydrous sodiumsulphate and solvent distilled under reduced
pressure to get O-Acyl compound. Yield 85%. 22
[0215] O-Acetate [16 m.moles], Aluminium chloride [20 m.moles],
were mixed together and heated to 145-50.degree. C. for 3 to 4 hrs.
protected from moisture. TLC after 4 hrs showed the absence of
starting material. Reaction mixture was cooled to room temperature
and poured to dil. hydrochloric acid and extracted with 2.times.50
ml of dichloromethane. Organic extract washed with water until the
washings are neutral to litmus. Solvent distilled off and the
residue chromatographed over silicagel using hexane:ethylacetate
[98:2] as eluent.
[0216] Yield of 2-Acylphenol is 72%. 23
[0217] Amalgamated Zinc [12 g], prepared according to standard
procedures was transferred to a three necked round bottomed flask
provided with a over head stirrer and a reflux condenser. Water [10
ml], Conc.Hydrochloric acid [20 ml] were added followed by 2-Acyl
phenol [10 m.moles] dissolved in 20 ml toluene. Ethanol [2 ml], was
added the reaction mixture stirred and refluxed. Conc.Hydrochloric
acid [3 to 4 ml], was added after every 3-4 hrs of reflux. Heating
stopped after 24 hrs of reflux. [TLC after 24 hrs of reflux
indicated the presence of Starting material. Addition of further
quantity of Zinc amalgam did not help]. Oraganic material extracted
with 2.times.35 ml toluene and the extracts washed with water until
washings neutral to litmus. Solvent distilled off under reduced
pressure and the residue chromatographed over silicagel, using
Hexane: Ethylacetate [97:3] as the eluent, to obtain the pure
product of formula (102).
[0218] Yield, 50-55%.
EXAMPLE 3
[0219] An agar incorporation test is carried out to determine the
MIC of various compounds shown in table 1
[0220] Medium:
[0221] Nutrient agar as test agar for bacteria:
[0222] Mueller hinton agar to cultivate the aerobic bacteria
[0223] Mueller hinton bouillon for obtaining the suspension of
microorganisms
[0224] Ethanol as solvent
[0225] Wilkins-Chalgren agar to cultivate the aerobic bacteria
[0226] Sabouraud glucose agar to cultivate the dermatophytes
[0227] Examples of Test bacteria
[0228] Staphylococcus aureusATCC 6538
[0229] Staphylococcus hominis DSM 20330
[0230] Escherichia coli NCTC 8196
[0231] Pseudomonas aeruginosa CIP A-22
[0232] Candida albicans ATCC 10231
[0233] Aspergillus niger ATCC 6275
[0234] Procedure:
[0235] The test substances are dissolved in ethanol, and a dilution
series of the compound of the formula (102) in agar are
prepared.
[0236] Anaerobic bacteria and dermatophytes are activated on
agar-plates, and washes off with Mueller-Hinton bouillon. Aerobic
bacteria are activated in Mueller-Hinton bouillon overnight. The
test germ suspension are diluted with Mueller-Hinton bouillon to a
density of McFarland standard 0.5.
[0237] 10 .mu.l of each germ suspension is dropped onto the agar
plates containing the test substance, and the plates are then
incubated at 37.degree. C. for 2 days. (Aerobic bacteria are
incubated at 36.degree. C. for 72 hours, anaerobic bacteria are
incubated at 30.degree. C. for 72 hours). As controls, the
bacterial suspensions are applied to agar plates without test
substances. In order to exclude the solvent ethanol having an
influence on the growth properties, the bacterial suspensions are
applied to agar plates containing ethanol, but without test
substance.
[0238] After the plates have been incubated, the growth of the
bacteria on the test-substance-containing plates is compared with
that on the control plates.
[0239] The minimum inhibitory concentration (MIC) is given as the
lowest concentration which shows clear inhibition compared with the
control.
[0240] The MIC values are given in the table 1 below.
1TABLE 1 Minimum Inhibitory Concentration [ppm] Comp. of Test
Organism formula Structure SH EC CA AN SA PA (103) 24 30 30 30 120
(104) 25 30 30 30 60 (105) 26 30 30 30 30 (106) 27 30 30 60 60
(107) 28 30 30 0 120 (108) 29 60 120 0 0 (109) 30 30 30 120 120
(110) 31 0 30 0 0 (111) 32 60 0 30 120 (112) 33 60 0 60 120 (113)
34 30 30 120 60 (114) 35 30 30 60 120 (115) 36 120 120 120 120
(116) 37 30 0 30 30 (117) 38 0 60 0 0 (118) 39 3 50 50 5 0 (119) 40
3 0 0 3 0 (120) 41 4 0 0 0 (121) 42 5 0 13 7 0 (122) 43 6 0 13 6 0
(123) 44 8 0 0 0 (124) 45 8 0 60 0 (125) 46 30 120 30 0 (103) 47 30
0 60 0 (126) 48 120 120 120 0 (127) 49 100 50 500 50 (128) 50 50 50
50 50 (129) 51 0 25 50 25 (130) 52 0 20 50 20 SA = Staphylococcus
aureus ATCC 6538 SH = Staphylococcus hominis DSM 20328 EC =
Escherichia coli NCTC 8196 PA = Pseudomonas aeruginosa CIP A-22 CA
= Candida albicans ATCC 10231 AN = Aspergillus niger ATCC 6275
[0241] The results in the above table clearly show that the
compounds have antimicrobial activity.
EXAMPLE 4
Preparation of Specific Diphenlyeter Compounds
[0242] The following compounds listed in table 2 are prepared by
the methods described in detail below:
2TABLE 2 Technique Comp. Synthetic used for of procedure MP
structure form Structure Name/CAS employed [.degree. C.] assignment
(107) 53 2-Phenoxyphenol 2417-10-9 Procedure I & IV 98 1.
.sup.1H-NMR 2. M.S. (113) 54 2-(2-Methyl)phenoxy- phenol 26321-31-3
Procedure I & IV -- 1. .sup.1H-NMR 2. M.S. (115) 55 2-(2-Ethyl)
phenoxyphenol 137610-67-4 Procedure I & IV -- 1. .sup.1H-NMR 2.
M.S. (112) 56 2-(2-Isopropyl)- phenoxyphenol Procedure I & IV
-- 1. .sup.1H-NMR 2. M.S. (111) 57 2-(2-sec-Butyl)- phenoxyphenol
Procedure I & IV -- 1. .sup.1H-NMR 2. M.S. (114) 58
2-(2-tert-Butyl)- phenoxyphenol Procedure I & IV -- 1.
.sup.1H-NMR 2. M.S. (131) 59 2-(4-Isopropyl)- phenoxyphenol
Procedure I & IV -- 1. .sup.1H-NMR 2. M.S. (117) 60
2-(4-Hydroxy phenoxy)phenol 23990-90-1 Procedure I & IV 155 1.
.sup.1H-NMR 2. M.S. (110) 61 4-Hydroxy-3-phenoxy- benzaldehyde
Procedure I & IV 118 --120 1. .sup.1H-NMR 2. M.S. (109) 62
2-Butanoyl-6- phenoxyphenol Procedure I, IV & VI A. -- 1.
.sup.1H-NMR 2. M.S. 63 4-Butanoyl-6- phenoxyphenol (108) 64
2-Propanoyl-6- phenoxyphenol Procedure I, IV & VI A. 94-97 1.
.sup.1H-NMR 2. M.S. 65 4-Propanoyl-6- phenoxyphenol (132) 66
2-Propanoyl-5- phenoxyphenol Procedure V, VI A/VI B. -- 1.
.sup.1H-NMR 2. M.S. (133) 67 2-Butanoyl-5- phenoxyphenol Procedure
V, VI A/VI B. 72-73 1. .sup.1H-NMR 2. M.S. (134) 68
2-(2-methyl-propan- oyl)5-phenoxyphenol Procedure V, VI A/VI B.
63-65 1. .sup.1H-NMR 2. M.S. (135) 69 2-Pentanoyl-5- phenoxyphenol
Procedure V, VI A/VI B. -- 1. .sup.1H-NMR 2. M.S. (136) 70
2-(3-Methyl butanoyl)- 5-phenoxyphenol Procedure V, VI A/VI B.
53-54 1. .sup.1H-NMR 2. M.S. (137) 71 2-Hexanoyl-5- phenoxyphenol
Procedure V, VI A/VI B. -- 1. .sup.1H-NMR 2. M.S. (138) 72
2-(1-Hydroxy-2- methylpropyl)-5- phenoxyphenol NaBH.sub.4reduction
of `16` -- 1. .sup.1H-NMR 2. M.S. (104) 73 2-Butyl-5-phenoxy-
phenol Procedure V, VI A/VI B & III/IV. -- 1. .sup.1H-NMR 2.
M.S. (103) 74 2-(2-Methylpropyl)-5- phenoxyphenol Procedure V, VI
A/VI B & III/VII. -- 1. .sup.1H-NMR 2. M.S. (106) 75
2-Pentyl-5-phenoxy- phenol Procedure V, VI A/VI B & III/VII --
1. .sup.1H-NMR 2. M.S. (139) 76 3-(2-Isopropyl)-5- phenoxyphenol
Procedure I & IV -- 1. .sup.1H-NMR 2. M.S. (116) 77
3-(2-sec-Butyl) phenoxyphenol Procedure I & IV -- 1.
.sup.1H-NMR 2. M.S. (126) 78 4-(4-Ethyl phenoxy)- phenol Procedure
I & IV -- 1. .sup.1H-NMR 2. M.S. (140) 79 4-(4-(3-Methyl
butyl)- phenoxy) phenol 35065-13-5 Procedure I & IV -- 1.
.sup.1H-NMR 2. M.S. (125) 80 4-(4-Propyl phenoxy)- phenol Procedure
I, II, IV & III/VII -- 1. .sup.1H-NMR 2. M.S. (141) 81
4-((3-Methyl butyl)- phenoxy)3-(3-methyl butyl)phenol Procedure I,
II, IV & III/VII -- 1. .sup.1H-NMR 2. M.S. (142) 82 4-(4-Nonyl
phenoxy)- phenol Procedure I, II, IV & III/VII 50-51 1.
.sup.1H-NMR 2. M.S. (143) 83 4-(2-Methylethyl-4-(2-
phenylethyl)phenoxy)- phenol Procedure I, II, IV & III/VII --
1. .sup.1H-NMR 2. M.S. (144) 84 4-(4-Propionyl phenoxy)phenol
Procedure I, II & IV -- 1. .sup.1H-NMR 2. M.S. (145) 85
4-(4-(2-Phenyl ethyl)- phenoxy)phenol Procedure I, II, IV &
III/VII 84-86 1. .sup.1H-NMR 2. M.S. (146) 86 4-(4-ethyl-2-
methylethyl-)phenoxy)- phenol Procedure I, II, IV & III/VII --
1. .sup.1H-NMR 2. M.S. (147) 87 4-Hydroxyl-5-(4- methylphenoxy)
benzaldehyde 136805-20-4 Procedure I & IV 88-90 1. .sup.1H-NMR
2. M.S. (148) 88 3-Hydroxyl-4-phenoxy benzaldehyde 35065-13-5
Procedure I & IV -- 1. .sup.1H-NMR 2. M.S. (149) 89
3-phenoxyphenol 713-68-8 Procedure V -- 1. .sup.1H-NMR 2. M.S.
(150) 90 3-(2-methyl phenoxy)phenol Procedure I & IV -- 1.
.sup.1H-NMR 2. M.S. (151) 91 3-(3-methyl phenoxy)phenol Procedure I
& IV -- 1. .sup.1H-NMR 2. M.S. (105) 92 2-Propyl-5-
phenoxyphenol Procedure V, VI A/VI B & III/VII -- 1.
.sup.1H-NMR 2. M.S. (152) 93 2-Propyl-5-(2- methylphenoxy)phenol
Procedure I, IV, VI A/VI B & III/VII -- 1. .sup.1H-NMR 2. M.S.
(153) 94 2-Propyl-5-(3- methylphenoxy)phenol Procedure I, IV, VI
A/VI B & III/VII -- 1. .sup.1H-NMR 2. M.S. (154) 95
2-phenoxy-2-(3- methylbutyl)phenol Procedure V, VI A/VI B &
III/VII -- 1. .sup.1H-NMR 2. M.S. (155) 96 2-(3-methylbutyl)-5-(3-
methylphenoxy)phenol Procedure I, II, IV & III/ VII -- 1.
.sup.1H-NMR 2. M.S. (156) 97 2-Hexyl-5-phenoxy phenol Procedure V,
VI A/VI B & III/VII -- 1. .sup.1H-NMR 2. M.S. (157) 98
2-(2-phenylethyl)-5- phenoxy phenol Procedure V, VI A/VI B &
III/VII 73-75.degree.C. 1. .sup.1H-NMR 2. M.S. (158) 99
2-(2-phenylethyl)-5-(2- methyl phenoxy) phenol Procedure I, IV, VI
A/VI B & III/VII -- 1. .sup.1H-NMR 2. M.S. (159) 100
2-(2-phenylethyl)-5-(3- methyl phenoxy) phenol Procedure I, IV, VI
A/VI B & III/VII -- 1. .sup.1H-NMR 2. M.S. (160) 101
2-(Dodecanoyl-5- phenoxy phenol Procedure V, VI A/VI B &
III/VII -- 1. .sup.1H-NMR 2. M.S. (161) 102 3-[4-(2-methyl
ethyl)]phenoxy phenol Procedure I & IV -- 1. .sup.1H-NMR 2.
M.S. (162) 103 4-(2-methylethyl-4- ethyl)phenoxy phenol Procedure
I, II, IV & III/ VII -- 1. .sup.1H-NMR 2. M.S. (127) 104
4-phenoxy phenol 831-82-3 Procedure I & IV 76-77 1. .sup.1H-NMR
2. M.S. (163) 105 4-(4-hydroxy)phenoxy phenol 1965-09-9 Procedure I
& IV -- 1. .sup.1H-NMR 2. M.S. (164) 106 3-(4-hydroxy)phenoxy
phenol 68100-19-6 Procedure I & IV 116-118 1. .sup.1H-NMR 2.
M.S.
[0243] General Synthesis of Hydroxydiphenylethers
[0244] General Procedure--I.
[0245] Example:
[0246] Ullmann condensations are carried out as per the procedure
outlined by R. G. R. Bacon and O. J. Stewart, J. Chem. Soc., 1965
4953.
[0247] To a stirred solution of o-cresol 21.6 g. (0.2 mol) in 110
ml N,N-dimethyl acetamide under nitrogen atmosphere, was added
o-bromoanisole 74.8 g (0.4 mole) followed by Cuprous oxide 28.62 g
(0.4 mole). Reaction mixture refluxed for 24 hr at 165-167.degree.
C. It was cooled to room temperature and poured to 1 l water
containing 100 ml concentrated HCl. Reaction mixture extracted with
3.times.150 mL ether. Organic extract washed with 10% NaOH solution
to remove unreacted cresol. Solvent and excess of o-bromoanisole
distilled off under reduced pressure. Product purified by
chromatography over silica gel column.
[0248] yield=28 g.
[0249] % yield by theory =65%
[0250] General catalysts for Ullmann condensation: Cu, Cu2Cl2, bas.
CuCO3, CuCl2, CuO, Cu2O, reaction in high boiling solvents as
Pyridin, DMF, DMA, DMSO, Toluene, Xylene and others, bases are
hydroxides/carbonates from group 1/2 metals
[0251] General Procedure--II
[0252] Example:
[0253] Acylation of Methoxy Diphenyl Ether.
[0254] Isovelaroyl chloride 1.2 g (0.01 mole) and ethylene
dichloride (10 ml) were mixed and cooled to 0.degree. C. with
stirring. Anhydrous AlCl.sub.3 2.7 g (0.02 mole) added portionwise
maintaining temp. below 5.degree. C. p-Methoxy diphenyl ether 2 g
(0.01 m) added dropwise during 15 minutes. Stirring continued for 1
hr at 0-5.degree. C. Reaction mixture added to 100 ml of cold water
with vigorous stirring, followed by extraction with 50 ml ethylene
dichloride. Organic layer separated, washed with 50 ml water and
dried briefly over anhy. Na.sub.2SO.sub.4 Solvent distilled under
reduced pressure to get the crude product. It was purified over
silica gel column using hexane:ethyl acetate as eluent.
[0255] Yield: 2.46 g.
[0256] % yield by theory: 85-90%
[0257] General Friedl-Crafts acylation catalysts: Lewis acids as
AlCl.sub.3, ZnC.sub.3, FeCl3, BCl.sub.3, BF.sub.3, transition metal
trifluorosulfonates (eg. Sc(OTf).sub.3)
[0258] reaction in inert solvents as EDC, CH.sub.2Cl.sub.2, CS2,
Nitrobenzene
[0259] General Pocedure--III
[0260] Example: 107
[0261] Hydrogenation of Keto to Methylene.
[0262] To a 125 ml autoclave, a solution of Keto compound 3.67 g
(0.01 mole) in 50 ml ethanol was charged, followed by 10 ml gl.
acetic acid, 10%Pd--C (5 mg), 0.1 ml perchloric acid and flushed
twice with hydrogen. Reaction mixture hydrogenated at an autoclave
temp. of 65.degree. C. and pressure of 100-110 psi for 4-6 hr.
Completion of the reaction was followed by TLC. Reaction mixture
cooled to room temperature, pressure released and filtered.
Filtrate was added to 200 ml water. Ethylene dichloride (100 ml)
was added, organic layer washed with 2.times.50 ml 5% NaHCO.sub.3
solution and dried over anhy. Na.sub.2SO.sub.4. Solvent distilled
off under reduced pressure to get the product.
[0263] Yield: 3.33 g.
[0264] % yield by theory: 90-95%
[0265] General Procedure--IV
[0266] Example: 108
[0267] Demethylation of Methoxy Ether to Phenol.
[0268] Methyl ether 14 g (0.065 mole), acetic acid 25 ml,
hydroiodic acid 25 ml, acetic anhydride 20 ml. were mixed and
refluxed under stirring at 105-110.degree. C. for 1 hr. Reaction
mixture poured into 1L ice cold water, decolorized with Sodium
sulphite solution, neutralized with saturated NaHCO.sub.3 Solution
(2.times.100 ml) and extracted with DCM (3.times.100 ml). Organic
layer washed with water, dried over Na.sub.2SO.sub.4. Crude
reaction mixture chromatographed over silica column to get the pure
product.
[0269] Yield: 10 g
[0270] % yield by theory: 75%
[0271] General Demethylating Agents as AlCl.sub.3, BCl.sub.3,
BF.sub.3, HBr, pyridinium.times.HCl
[0272] General Procedure--V
[0273] Example: 109
[0274] Preparation of m-phenoxyphenol
[0275] To a stirred solution of 49.5 g (0.45 mol) of resorcinol in
75 ml dry pyridine under nitrogen atmosphere, 16.2 g (0.3 mol) of
Sodium methoxide was added. Heating started and methanol
fractionally distilled off over a period of 0.5 hr. Bromobenzene,
142 g (0.9 mole) was run in to the reaction mixture followed by 2.2
g, of Cuprous chloride. Reaction mixture heated under reflux for
3-4 hr, pyridine distilled off while the pot temperature rose to
150.degree. C. The residue was poured into 50 ml conc. HCl in 120
ml water and stirred. Organic material extracted in 200 ml benzene
followed by washing with 25 ml of 20% HCl. Organic layer extracted
with 100 ml of 10% NaOH solution followed by a second extraction
with 20 ml of 10% NaOH. The combined aqueous extracts were
acidified with, HCl.sub.conc, liberated m-phenoxy phenol was
extracted into benzene (300 ml). From the organic layer benzene was
removed by distillation. Crude product purified by filtration over
a column of silica.
[0276] Yield: 35 g
[0277] % yield by theory: 40-42%
[0278] Catalysts for Ullmann condensation see Proc. I
[0279] General Procedure--VI-A
[0280] Example: 110
[0281] Acylation of m-phenoxy Phenol
[0282] Hexanoic acid 12.87 g (0.11 mole) added to fused ZnCl.sub.2,
6.50 g (0.15 mol), dissolved at 145-150.degree. C. To the above
reaction mixture m-phenoxy phenol 5.9 g (0.032 mol) was added.
Reaction mass stirred at 145-150.degree. c. for 3 hr. It was cooled
to room temperature and poured over 250 ml cold water, washed with
sat. NaHCO.sub.3 solution (2.times.150 ml), extracted with ethyl
acetate (2.times.100 ml). Organic extract dried over
Na.sub.2SO.sub.4. Solvent distilled off under reduced Pressure.
Crude product purified by chromatography over silica gel.
[0283] Yield: 2.5 g.
[0284] % yield by theory: 25-30%
[0285] General Procedure--VI-B
[0286] Example: 111
[0287] O-acylation of m-phenoxyphenol
[0288] Hexanoyl chloride 7.70 g (57.24 mmol) in 250 ml dry toluene
was stirred with activated Zn dust 3.74 g (57.24 mmol) at room
temperature for 15 minutes, m-phenoxy phenol 4.5 g (24.2 M mole) in
150 ml toluene added and the reaction mixture stirred at 70 to
75.degree. C. for 30 minutes. Reaction mixture cooled to room
temperature & filtered. Organic layer washed with 100 ml of 20%
K.sub.2CO.sub.3 Solution followed by second washing with 15 ml of
20% K.sub.2CO.sub.3 Solution. Toluene layer washed with water,
dried over Na.sub.2SO.sub.4. Solvent distilled off under reduced
pressure to get the product.
[0289] Yield: 6 g.
[0290] % yield by theory: 85%
[0291] Acylation also with carboxylic acid anhydrides
[0292] Fries Rearrangement
[0293] O-hexanoate 0.8 g (2.81 mmol) and AlCl.sub.3 0.45 g (3.47
mmol) were mixed together in a round bottom flask. After 4 hr at
145-150.degree. C., reaction mixture cooled to room temperature and
worked up by pouring over 50 ml 1:1 HCl (50 ml) followed by
extraction in DCM (100 ml). Organic layer washed with water.
Solvent evaporated off under reduced pressure. Crude reaction mass
purified by silica gel column chromatography to get the pure
product.
[0294] Yield: 0.6 g
[0295] % yield by theory: 75%
[0296] General Procedure--VII
[0297] Example: 112
[0298] Reduction of Keto to Methylene by Clemmenson's Method
[0299] Zinc amalgam was prepared from 12 g of Zn dust, 0.9 g of
mercury (II) chloride in 20 ml water and 2-3 ml HCl.sub.conc. This
was added to the solution of keto compd 1.5 g (5.28 mmol) in 25 ml
of toluene & 20 ml HCl.sub.conc. HCl gas bubbled into reaction
mixture for 2 hr. 50 ml of toluene was added and toluene layer
separated and washed with water. Solvent distilled off under
reduced pressure to get the product.
[0300] Yield:1.45 g
[0301] % yield by theory =85-90%
[0302] Reduction also succeeds with H.sub.2. see Proc. III
EXAMPLE 5
Preparation of the Compound of Formula
[0303] 113 114
EXAMPLE 6
Preparation of Compound of Formula
[0304] 115 116
EXAMPLE 7
Preparation of Compound of Formula
[0305] 117 118
3TABLE 3 m/e 1H NMR Compound Reaction Protocols (M + 1) (d ppm) 119
General procedure V, VIA/VIB & III/ VII 229 0.9-1.0 (t, 3H,
Me), 1.55-1.65 (m, 2H, --CH.sub.2--), 2.4-2.5 (t, 2H,
--CH.sub.2--), 4.8 (s, 1H, --OH), 6.4-6.45 (d, 1H, H.sup.6 Ar--H),
6.45--6.50 (dd, 1H, H.sup.4 Ar--H), 6.95-7.05 (m, 4H, H.sup.2',
H.sup.3', H.sup.5'H.sup.6' Ar--H), 7.25 (d, 1H, H.sup.3 Ar--H),
7.25-7.3 (m, 1H, H.sup.4' Ar--H) 120 General procedure V, VIA/VIB
& III/VII 257 0.9-1.0 (d, 6H, iso-pr), 1.4-1.55 (m, 2H,
>CH.sub.2, >CH---), 2.6 (t, 2H, --CH.sub.2--), 4.8 (s, 1H,
--OH), 6.4 (d, 1H, H.sup.6 Ar--H), 6.55-6.60(dd, 1H, H.sup.4
Ar--H), 6.9-7.05 (m, 4H, H.sup.2', H.sup.3', H.sup.5',
H.sup.6'Ar--H), 7.25 (d, 1H, H.sup.3 Ar--H), 7.25-7.3 (m, 1H,
H.sup.4' Ar--H) 121 General procedure V, VIA/VIB & III/VII 271
0.9-1.0 (t, 3H, Me), 1.2-1.4 (m, 6H, --CH.sub.2--), 1.45-1.65 (m,
2H, --CH.sub.2--), 2.45-2.6 (t, 2H, --CH.sub.2--), 5.0 (s, 1H,
--OH), 6.4-6.5 (d, 1H, H.sup.6 Ar--H), 6.50-6.60 (dd, 1H, H.sup.4
Ar--H), 6.9-7.2 (m, 4H, H.sup.2', H.sup.3', H.sup.5',
H.sup.6'Ar--H), 7.3 (d, 1H, H.sup.3 Ar--H), 7.4 (m, 1H, # H.sup.4'
Ar--H)
EXAMPLE 8
Synthesis of 4-(2.5-Dialkylphenoxy)-phenols
[0306] 122
[0307] The mixture of 0.05 mol 2,5-Dialkylphenol, 2.8 g (0.05 mol)
KOH, 0.4 g (0.006 mol) copper powder and 50 g (0.25 mol) bromo
anisole is heated in a standard reaction apparatus, equipped with a
water trap, to 160.degree. C. for 5 h. After cooling the reaction
mass is suspended in toluene and filtrated. After distilling off
the solvent and excess reagent the product is isolated by
distillation at 125.degree. C./0.01 mbar
4 R.sub.1 R.sub.2 Yield Me Me 4.6 g (40%) Me i-Propyl 6.4 9 (50%)
123 124
[0308] 0.02 mol of the 4-(2,5-Dialkylphenoxy)-methoxybenzene and 30
ml HBr (47% solution in water) are heated to reflux in 100 ml
acetic acid for 4 h. After cooling and distilling off acetic acid
the reaction mass is dissolved in 100 ml methylene chloride and
washed with 200 ml water with pH adjusted to pH 10 with 10% NaOH.
Produkt is isolated from the organic phase by distillation at
160.degree. C./0.01 mbar, colourless oils.
5 R.sub.1 R.sub.2 Yield Me Me 2.2 g (52%) Me i-Propyl 2.4 g
(60%)
[0309] Data R.sub.1=R.sub.2=Me:
[0310] Elementary Analysis:
6 C H O calc. 78.48 6.59 14.93 found 77.84 6.58 15.19
[0311] 1H-NMR (CDCl.sub.3): 2.15 (3H, s, CH.sub.3), 2.20 (3H, s,
CH.sub.3), 4.65 (1H, s, OH), 6.55-7.05 (7H, m, arom. H)
[0312] Mass spectrum: m/z [M+.]=214
[0313] Data R.sub.1=Me, R.sub.2=i-Propyl:
[0314] Elementary Analysis:
7 C H O calc. 79.30 7.49 13.21 found 77.82 7.30 13.61
[0315] 1H-NMR (CDCl.sub.3): 1.05 (3H, s, CH.sub.3), 1.08 (3H, s,
CH.sub.3), 2.10 (3H, s, CH.sub.3), 2.70 (1H, s, CH), 4.85 (1H, s,
OH), 6.60-7.05 (7H, m, arom. H)
[0316] Mass spectrum: m/z [M+.]=242
EXAMPLE 9
Synthesis of 4-(2-t-Butyl-5-methylphenoxy)phenol
[0317] 125
[0318] The mixture of 16.4 g (0.1 mol) 2-t-butyl-5-methylphenol and
1.8 g (0.03 mol) KOH in 100 ml xylene is heated in a standard
reaction apparatus, equipped with a water trap, to reflux until no
more water is distilling. After addition of 0.2 g basic copper
carbonate and 18.7 g (0.1 mol) bromo anisole the mixture is heated
to reflux for 20 h. After cooling the reaction mass is filtrated
and solvent and excess reagents are distilled off. The product is
isolated by distillation at 100.degree. C./0.01 mbar.
[0319] Yield: 7.1 g (81%). 126
[0320] 7.1 g (0.026 mol) of
4-(2-t-Butyl-5-methylphenoxy)-methoxybenzene are heated with 15.0 g
(0.13 mol) pyridinium hydrochloride to 180.degree. C. for 6 h.
After cooling water is added and the reaction mass is extracted
with xylene. The product is distilled after evaporation of xylene
at 130.degree. C./0.01 Torr and recrystallized from petrol ether
(80-110) to yield colourless crystals (mp 102.degree. C.).
[0321] Yield: 4.6 g (69%)
[0322] Elementary Analysis:
8 C H O calc. 79.65 7.86 12.48 found 78.96 7.55 11.59
[0323] 1H-NMR (CDCl.sub.3): 1.41 (9H, s, C(CH.sub.3).sub.3), 2.21
(3H, s, CH.sub.3), 4.75 (1H, s, OH), 6.58-7.25 (7H, m, arom. H)
[0324] Mass spectrum: m/z [M+.]=256
[0325] Microbiological Data of the Above Compounds (MIC in
ppm):
9 TABLE 4 Substance R.sub.1 = t-Butyl R.sub.1 = Me R.sub.1 =
R.sub.2 = Microorganisms R.sub.2 = Me R.sub.2 = i-Propyl Me
Staphylococcus aureus ATCC 6538 6.75 ppm 6.25 ppm 50.0 ppm
Staphylococcus epidermidis ATCC 12228 3.4 ppm 6.25 ppm 25.0 ppm
Corynebacterium xerosis ATCC 373/ATCC 7711 3.4 ppm 3.125 ppm 25.0
ppm Staphylococcus hominis DSM 20328 6.25 ppm -- Corynebacterium
minutissimum ATCC 23348 3.4 ppm 6.25 ppm 25.0 ppm Propionibacterium
acnes ATCC 11829 5 ppm 10 ppm -- Escherichia coli NCTC 8196 >100
ppm >200 ppm >200 ppm Proteus vulgaris >100 ppm >200
ppm >200 ppm ATCC 6896 Pseudomonas aeruginosa >100 ppm
>200 ppm >200 ppm CIP A-22 Candida albicans 12.5 ppm 12.5 ppm
25.0 ppm ATCC 10231 Aspergillus niger 6.75 ppm 50 ppm -- ATCC 6275
Epidermophyton floccosum 1.65 ppm <3.125 ppm -- CBS 55384
Trichophyton mentagrophytes ATCC 9553 3.4 ppm 6.25 ppm --
Trichophyton rubrum 10 ppm 5 ppm -- DSM 4167 Malassezia furfur 2.5
ppm -- -- DSM 6171 Actinomyces viscosum 5 ppm 80 ppm -- DSM 43329
Porphyromonas gingivalis 1.25 ppm 5 ppm -- DSM 20709 Selenomonas
artemidis ATCC 43528 5 ppm 10 ppm -- Streptococcus sobrinus 5 ppm 5
ppm -- DSM 20742
* * * * *