 |
Description  |
|
|
TECHNICAL FIELD
The present invention relates to .alpha.-hydroperoxyisopropylphenyl
compounds and a process for preparing the same.
Furthermore, the invention is concerned with test compositions for the
measurement of peroxide-active substances using as organic hydroperoxide
the above-mentioned .alpha.-hydroperoxyisopropylphenyl compounds and test
devices carrying said compositions.
The .alpha.-hydroperoxyisopropylphenyl compounds and the compositions or
test devices containing the same are effectively utilized for detecting
peroxide-active substances such as blood or hemoglobin.
It may be presumed that if blood or hemoglobin is contained in urine, feces
or vomit, certain disease such as inflammation or ulcer progresses in the
urinary organs or the digestive system such as the kidneys, the stomach or
the intestines. Therefore, in order to promptly diagnose and treat such
disease correct detection of blood or hemoglobin (occult blood) in urine,
feces or vomit as mentioned above is important. The
.alpha.-hydroperoxyisopropylphenyl compounds of the invention are
favorably used as a reagent for the examination of such occult blood.
BACKGROUND ART
Test devices for the detection of occult blood are constituted of a carrier
in which organic hydroperoxide, coloration indicator, buffering agent,
wetting agent, activating agent and stabilizer are impregnated. If
hemoglobin is present in a specimen, the organic hydroperoxide is
activated to produce nascent oxygen with which the indicator is oxidized
and develops color. As the organic hydroperoxide are known
2,5-dimethylhexane-2,5-dihydroperoxide and cumene hydroperoxide. Whereas
these peroxides are in practical use, they are disadvantageous in
remarkably reducing of the detective sensitivity due to lack of stability
with elapse of time, pseudonegative judgement when vitamin C is contained
in the urine specimen, reduction of capacity in the multi-item test pieces
for the detection of urinary components caused by discoloration of the
adjacent test pieces, low coloration sensitivity, etc. Compounds in which
the benzene ring of cumene hydroperoxide is provided with a substituent
such as a C.sub.1-6 alkyl group, Cl, Br, I, NO.sub.2 or carboxyl group
have recently been proposed as the hydroperoxide with which these
disadvantages are improved (Japanese Patent LOP Publication No.
190663/1984). Although the peroxides represent considerable improvement
over the known compounds, the stability with elapse of time is not yet
satisfactory.
DISCLOSURE OF THE INVENTION
First, it is an object of the invention to provide peroxides without the
above-mentioned disadvantages and a process for preparing the same.
Second, another object of the invention is to provide test compositions for
the measurement of peroxide-active substances without the above-mentioned
disadvantages and test devices carrying the same.
These objects are achieved by the present invention as set forth below.
(1) An .alpha.-hydroxyperoxyisopropylphenyl compound having the general
formula (I) or (II)
##STR1##
wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different and
respectively represent hydrogen atom, a lower alkyl group, a halogen atom,
carboxyl group, nitro group or a straight- or branched-chain
oxygen-containing alkyl group having one or more ether bonds in the chain
or a monovalent organic group containing sulfur atom provided that at
least one of R.sup.1, R.sup.2 and R.sup.3 represents the above-mentioned
straight- or branched-chain oxygen-containing alkyl group or a monovalent
organic group containing sulfur atom; X represents a straight- or
branched-chain alkylene group which may contain ether bond and/or
phenylene group in the chain or a divalent organic group containing sulfur
atom and R.sup.4 and R.sup.5 are the same or different and respectively
represent hydrogen atom, a lower alkyl group, a halogen atom, carboxyl
group or nitro group.
(2) A compound of the formula (I) according to item 1 wherein the
oxygen-containing alkyl group in R.sup.1 -R.sup.3 is a group having 2-100
carbon atoms.
(3) A compound of the formula (I) according to item 1 wherein the
oxygen-containing alkyl group in R.sup.1 -R.sup.3 is an alkyl group
represented by the formula given below.
##STR2##
R.sup.7 -R.sup.8 being the same or different and respectively representing
hydrogen atom or a lower alkyl group, or
##STR3##
(4) A compound of the formula (I) according to item 1 wherein the organic
group in R.sup.1 -R.sup.3 is a sulfonyl group represented by the formula
given below.
##STR4##
in which R.sup.9 represents a straight- or branched-chain alkyl group,
R.sup.10 and R.sup.11 are the same or different and respectively represent
a straight- or branched-chain alkyl group or, together with nitrogen atom
with which they are bonded, represent a five- or six-membered heterocyclic
group which may additionally have oxygen atom, sulfur atom or nitrogen
atom in the ring, Y represents a straight- or branched-chain alkylene
group and C represents an integer from 0 to 5.
(5) A compound of the general formula (II) according to item 1 wherein the
alkylene group in X is a group having 2-100 carbon atoms.
(6) A compound of the general formula (II) according to item 1 wherein the
alkylene group in X is an alkylene group represented by the formula given
below.
##STR5##
(7) a compound of the formula (II) according to item 1 wherein the organic
group in X is represented by the formula given below.
##STR6##
in which f and g respectively represent an integer from 0 to 5 and each of
R.sup.12 and R.sup.13 represents a straight- or branched-chain alkyl
group.
(8) A process for preparing .alpha.-hydroperoxyisopropylphenyl compounds
having the general formula (I) or (II) according to item 1 which comprises
oxidizing with an aqueous solution of hydrogen peroxide an
.alpha.-hydroxyisopropylphenyl compound having the general formula (II) or
(IV)
##STR7##
wherein R.sup.1 -R.sup.5 and X respectively have the same meanings as
defined in item 1.
(9) A test composition for the measurement of peroxide-active substances
comprising an .alpha.-hydroperoxyisopropylphenyl compound having the
general formula (I) or (II) according to item 1 and an oxidation
coloration indicator.
(10) A composition according to item 9 wherein the oxidation coloration
indicator is orthotolidine, benzidine or leucomalachite green.
(11) A test device for the measurement of peroxide-active substances
comprising a carrier on which a composition containing an
.alpha.-hydroperoxyisopropylphenyl compound having the general formula (I)
or (II) according to item 1 and an oxidation coloration indicator is
carried.
(12) A test device according to item 11 wherein the carrier is non-woven
cloth made of filter paper, glass fibers or a plastic material.
In the above-mentioned formula (I), as described above, R.sup.1, R.sup.2
and R.sup.3 are the same or different and respectively represent hydrogen
atom, a lower alkyl group, a halogen atom, carboxyl group, nitro group or
a straight- or branched-chain oxygen-containing alkyl group containing one
or more ether bonds in the chain or a monovalent organic group containing
sulfur atom provided that at least one of R.sup.1, R.sup.2 and R.sup.3
represents the oxygen-containing alkyl group or the organic group. The
oxygen-containing alkyl group may be either in straight chain or in
branched chain but is required to contain one or more ether bonds in the
chain. Number of the carbon atoms in the alkyl group is 2-100, preferably
2-50, although it is not particularly limited. Number of the ethers
present in the oxygen-containing alkyl group is preferably 1 -7, although
there is no limitation to it so far as it is one or more. Said alkyl group
may further be substituted with those substituents which will not
interfere with coloration of the above-mentioned coloration indicator, for
example, halogen atoms (Cl, Br, I), nitro group, hydroxyl group, sulfone
group, carboxyl group, amide group, phenyl group, substituted phenyl
group, etc. Preferred examples of such alkyl group are:
2,4,7-Trioxaoctyl,
2,5,8,11,14,16,19-Heptaoxaeicosanyl,
Methyl-polyethylene glycol-methyl
##STR8##
8-Hydroxy-4-oxaoctyl, 1,1-Dimethyl-2,4,7-trioxaoctyl,
2-Oxa-3-phenylpropyl,
(Substituted)phenoxymethyl, and
1,1,3,3-Tetramethylbutyl-polyethylene glycol-methyl
##STR9##
It is desirable that the monovalent organic group
containing sulfur atom contains sulfonyl group
##STR10##
As preferred examples of said group are mentioned groups having the
formula given below.
##STR11##
R.sup.9 in the above-mentioned formula is a straight- or branched-chain
alkyl group containing preferably 1-8 carbon atoms, examples of which
include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl,
n-hexyl, n-heptyl, n-octyl and the like.
R.sup.10 and R.sup.11 are the same or different and respectively represent
a straight- or branched-chain alkyl group containing preferably 1-4 carbon
atoms, examples of which include methyl, ethyl, n-propyl, i-propyl,
n-butyl and i-butyl.
Alternatively, R.sup.10 and R.sup.11, together with the nitrogen atom with
which they are bonded, represent a 5- or 6-membered heterocyclic group,
examples of which include morpholyl, piperazyl, piperidyl and the like.
Y is an alkylene group containing preferably 1-4 carbon atoms which
include, for example, methylene, ethylene, trimethylene, propylene or
n-butylene.
c is an integer of preferably 1 or 2.
As especially preferred examples of the monovalent organic group containing
sulfur atom are mentioned:
n-Butylsulfonyl
##STR12##
In the above-mentioned formula (II) X represents an alkylene group which
may optionally contain ether bond and/or phenylene group in the chain or
it represents a divalent organic group containing sulfur atom.
The alkylene group may be either in straight chain or in branched chain and
contain in the chain one or more, preferably 1-7 ether bonds. Moreover,
said alkylene group may contain phenylene group in the chain. In addition,
said alkylene group may be substituted with those substituents which will
not interfere with color development of the coloration indicator mentioned
above, for example, halogen atoms (Cl, Br, I), nitro group, hydroxyl
group, sulfone group, carboxyl group, amide group, phenyl group,
substituted phenyl group and the like.
As preferred examples of the above-mentioned alkylene group are mentioned:
Trimethylene,
2,2-(3,5,8-Trioxa)nonanylene,
1,7-(4-Hydroxy)heptanylene,
1,3-(2-Oxa)propylene,
1,12-(2,5,8,11-Tetraoxa)decanylene,
1,21-(2,5,8,11,14,17,20-Heptaoxa)heneicosanylene,
Polyethylene glycolyl (mean value for the degree of polymerization 13),
1,14-(2,13-Dioxa)tetradecanylene
##STR13##
1,4-Bis[1-(2-oxa-3-propylene)]phenyl,
1,13-(7-Hydroxy-4,10-dioxa)tridecanylene,
1,6-(2,5-Dioxa)heptanylene and the like.
As preferred examples of the divalent organic group containing sulfur atom
in the chain are mentioned groups having the formula set forth below.
##STR14##
In the above formulae f and g are respectively an integer from 0 to 5,
preferably from 0 to 2. Each of R.sup.12 and R.sup.13 is a straight- or
branched-chain alkyl group having preferably 1-4 carbon atoms, methyl,
ethyl or n-propyl being particularly preferable.
As especially preferred examples of the above-mentioned divalent organic
group containing sulfur atom are mentioned:
##STR15##
Methylenesulfonylethylenesulfonylethylenesulfonylmethylene
##STR16##
Sulfonyl-N-methylaminoethoxyethoxyethyl-N-methylaminosulfonyl
##STR17##
Sulfonyl-N-methylaminoethoxyethoxyethoxyethoxy-ethoxyethyl-N-methylaminosul
fonyl
##STR18##
As typical compounds of the .alpha.-hydroperoxyisopropylphenyl compounds
according to the invention are mentioned:
4-(2,4,7-Trioxaoctyl)cumene hydroperoxide,
4-(2,5,8,11,14,16,19-Heptaoxaeicosanyl)cumene hydroperoxide,
Polyethylene glycol 4-(.alpha.-hydroperoxyisopropyl)-benzylmethyl ether,
4-(8-Hydroxy-4-oxaoctyl)cumene hydroperoxide,
3-(1,1-Dimethyl-2,4,7-trioxaoctyl)cumene hydroperoxide,
4-(.alpha.-Hydroperoxyisopropyl)benzyl benzyl ether,
4-(.alpha.-Hydroperoxyisopropyl)benzyl 4-nitrobenzyl
4-(.alpha.-Hydroperoxyisopropyl)benzyl 3,4,5-trimethoxyphenyl ether,
Polyethylene glycol 4-(.alpha.-hydroperoxyisopropyl)benzyl
4-(1,1,3,3-tetramethylbutyl)phenyl ether,
3,4-Bis(2,5,8,11,14-pentaoxapentadecanyl)cumene hydroperoxide,
3,4,5-Tris(2-oxa-3-phenylpropyl)cumene hydroperoxide,
1-Chloro-4-(.alpha.-hydroperoxyisopropyl)-2-(2-methoxyethoxymethoxymethyl)b
enzene,
4-(.alpha.-Hydroperoxyisopropyl)-2-methylbenzyl benzyl ether,
4-(.alpha.-Hydroperoxyisopropyl)-2,6-dichlorobenzyl benzyl ether,
1,3-Bis[4-(.alpha.-hydroperoxyisopropyl)phenyl]propane,
2,2-Bis[4-(.alpha.-hydroperoxyisopropyl)phenyl]-3,5,8-trioxanonane,
1,7-Bis[4-(.alpha.-hydroperoxyisopropyl)phenyl]-4-hydroxyheptane,
4-(.alpha.-Hydroperoxyisopropyl)benzyl ether
20
1,12-Bis[4-(.alpha.-hydroperoxyisopropyl)phenyl]-2,5,8,11-tetraoxadodecane
1,21-Bis[4-(.alpha.-hydroperoxyisopropyl)phenyl]-2,5,8,11,14,17,20-heptaoxa
heneicosane,
Polyethylene glycol bis[4-(.alpha.-hydroperoxyisopropyl)benzyl]ether,
1,14-Bis[4-(.alpha.-hydroperoxyisopropyl)phenyl]-2,13-dioxatetradecane,
1,4-Bis[3-[4-(.alpha.-hydroperoxyisopropyl)phenyl]-2-oxapropyl]benzene
1,13-Bis[4-(.alpha.-hydroperoxyisopropyl)phenyl]-7-hydroxy-4,10-dioxatridec
ane,
1,6-Bis[3-(.alpha.-hydroperoxyisopropyl)phenyl]-2,5-dioxaheptane,
Bis[2-chloro-4-(.alpha.-hydroperoxyisopropyl)benzyl]ether,
1,9-Bis[2-chloro-4-(.alpha.-hydroperoxyisopropyl)-phenyl]-2,5,8-trioxanonan
e,
1,21-Bis[4-(.alpha.-hydroperoxyisopropyl)-2-methylphenyl]-2,5,8,11,14,17,20
-heptaoxaheneicosane,
1-[4-(.alpha.-Hydroperoxyisopropyl)benzenesulfonyl]-butane,
N,N-Dimethyl-[4-(.alpha.-hydroperoxyisopropyl)-benzene]sulfoamide,
1-[4-(.alpha.-Hydroperoxyisopropyl)benzene]sulfonyl-3,5,8-trioxanonane,
N-[4-(.alpha.-Hydroperoxyisopropyl)benzenesulfonyl]-morpholine,
N,N'-Bis[4-(.alpha.-hydroperoxyisopropyl)benzenesulfonyl]piperazine,
Bis[4-(.alpha.-hydroperoxyisopropyl)benzyl]sulfone,
2-[2-[.alpha.-[4-(.alpha.-Hydroperoxyisopropyl)toluene]-sulfonyl]ethanesulf
onyl]ethanesulfonylmethyl-4-(.alpha.-Hydroperoxyisopropyl)benzene,
N,N'-Bis[4-(.alpha.-hydroperoxyisopropyl)benzenesulfonyl]-N,N'-dimethyl-3,6
,9-trioxaundecane-1,11-diamine, and
N,N'-Bis[4-(.alpha.-hydroperoxyisopropyl)-benzenesulfonyl]-N,N'-dimethyl-3,
6,9,12,15-pentaoxaheptadecane-1,17-diamine.
The .alpha.-hydroperoxyisopropylphenyl compounds represented by the
above-mentioned formula (I) or (II) according to the invention are novel
compounds and are prepared by oxidizing under acid conditions an
.alpha.-hydroperoxyisopropylphenyl compound represented by the
above-mentioned formula (III) or (IV) in an aqueous solution of hydrogen
peroxide. Preferably, the .alpha.-hydroperoxyisopropylphenyl compound
(III) or (IV) is dissolved in an appropriate organic solvent such as
ether, and to the solution are added 30% or 50% aqueous solution of
hydrogen peroxide and a small amount of a mineral acid such as sulfuric or
hydrochloric acid. The mixture is reacted at room temperature for ten and
odd hours. After completion of the reaction, the desired product is
isolated from the reaction product in a conventional manner. For example,
water is added to the reaction mixture, which is then extracted with an
appropriate organic solvent such as ethyl acetate. The solvent is
distilled off from the extract, and the residue is purified by such means
as column chromatography to obtain the desired product.
The .alpha.-hydroperoxyisopropylphenyl compounds (III) or (IV) are produced
by reacting a phenyl compound represented by the general formula (V) or
(VI)
##STR19##
wherein R.sup.1 -R.sup.5 and X respectively have the same meaning as
defined above and Z is a halogen atom with n-butyllithium (or magnesium)
and then with acetone. For example, the two compounds are reacted in an
appropriate organic solvent such as, for example, tetrahydrofuran or
diethyl ether at -78.degree. C. (in case of n-butyllithium) or a
temperature from room temperature to refluxing condition (in case of
magnesium) followed by addition of acetone to produce the compound (III)
or (IV).
As described above, the .alpha.-hydroperoxyisopropylphenyl compounds (I) or
(II) of the invention are used as peroxide in the measurement of
peroxide-active substances, and especially useful for detecting occult
blood in urine, feces and vomit.
The test devices comprise a carrier on which a composition constituted of
the .alpha.-hydroperoxyisopropylphenyl compound (I) or (II) of the
invention, a coloration indicator, and if needed, buffering agent, wetting
agent, activating agent, stabilizer and solvent is impregnated.
As the indicator is used a so-called oxidation indicator develops color by
oxidation. As examples are mentioned orthotolidine, benzidine,
leucomalachite green and the like.
The buffering agent is employed for maintaining a constant pH values on the
test device. Preferred agents are, for example, citrate, malonate or
succinate that can maintain pH value in the range of 4-8 when the test
device is soaked in a sample. The wetting agent is used in order that the
sample solution will uniformly be wetted when the test device is soaked in
a sample and is preferably exemplified by surface-active agents such as
sodium laurylsulfate, sodium dodecylbenzenesulfonate and sodium
dioctylsulfosuccinate. The activating agent is used for enhancing
sensitivity of the color-developing reaction on the test device and
preferably is 3-aminoquinoline, quinine, isoquinoline or the like. As the
stabilizer is used a thickener for preventing elution of the test reagents
from the test device, which is preferably a polymer such as polyvinyl
alcohol, polyvinylprrolidone or polyethylene glycol, or gelatin or gum
arabic. The solvent may be any of those in which a mixture of the
above-mentioned reagents is readily soluble, and ethyl alcohol, acetone,
benzene, toluene, chloroform and the like are advantageously employed. The
carrier may be any one being neither soluble in nor reactive with the
above-mentioned solvent and capable of absorbing the above-mentioned
composition, a non-woven cloth composed of filter paper, glass fibers or a
plastic material being desirable.
Amounts of the .alpha.-hydroperoxyisopropylphenyl compound and other
reagents used in the above-mentioned test composition and test device are
not critical but appropriately determined with reference to prior art. As
a matter of fact, they are selected so as to be sufficient to cause
reaction with the subject peroxide-active substance and color-developing
reaction.
The invention will be described below in more particular with reference to
examples and test examples.
EXAMPLE 1
4-(2,4,7,-Trioxaoctyl)cumene hydroperoxide
##STR20##
To a solution of 4.56 g (24.4 mmol) of 4-bromobenzyl alcohol in dry
dichloromethane (48 ml) were added in an atmosphere of argon 3.32 ml (29.1
mmol) .beta.-methoxyethoxymethyl chloride and 6.40 ml (36.7 mmol) of
N,N-diisopropylethylamine, and the mixture was allowed to react at room
temperature for 15 hours. To the resulting solution was added water
followed by extraction with dichloromethane. The organic layer was washed
with water and concentrated under reduced pressure. The residue thus
obtained was subjected to silica gel column chromatography for separation
and purification. Elution with dichloromethane yielded 6.18 g (22.5 mmol)
of 4-bromo-1-(2,4,7-trioxaoctyl)benzene.
To a solution of 6.18 g (22.5 mmol) of the above-obtained compound in dry
tetrahydrofuran (180 ml) was added 1.60M hexane solution of n-butyllithium
in the atmosphere of argon at -78.degree. C., and the mixture was allowed
to react for 30 min. To the resulting solution was added 8.3 ml (113 mmol)
of acetone, and the mixture was reacted at -78.degree. C. for 10 min.
followed by addition of saturated aqueous solution of ammonium chloride
and extraction with ethyl acetate. The organic layer was washed with water
and subjected to concentration under reduced pressure. The residue thus
obtained was subjected to silica gel column chromatography for separation
and purification. Elution with dichloromethane-methanol (25:1) yielded
3.78 g (14.9 mmol) of
1-(.alpha.-hydroxyisopropyl)-4-(2,4,7-trioxaoctyl)benzene.
To 3.78 g (14.9 mmol) of the above-obtained hydroxy compound were added 10
ml of ether, 20 ml of 30% aqueous solution of hydrogen peroxide and 0.500
ml of concentrated sulfuric acid, and the mixture was allowed to react at
room temperature for 18 hours followed by addition of water and extraction
with ethyl acetate. The organic layer was washed with water and
concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with ethyl acetate-hexane (1:1) yielded 3.30 g (12.2
mmol) of 4-(2,4,7-trioxaoctyl)cumene hydroperoxide.
NMR (ppm, CDCl.sub.3)
8.22(s, 1 H), 7.48-7.17(m, 4 H), 4.73(s, 2 H),
4.57(s, 2 H), 3.82-3.43(m, 4 H), 3.35(s, 3 H),
1.57(s, 6 H).
IR(.nu.cm.sup.-1,CHCl.sub.3) 3530, 3330.
EXAMPLE 2
4-(2,5,8,11,14,16,19-Heptaoxaeicosanyl)cumene hydroperoxide
##STR21##
To a solution of 1.49 g (37.3 mmol) of sodium hydride contained at 60% in
mineral oil in dry dimethylformamide (70 ml) was added 7.00 g (24.8 mmol)
of 3,6,9,12,14,17-hexaoxaoctadeca-1-nol in an atmosphere of argon, and the
mixture was allowed to react at 40.degree.-50.degree. C. for 30 min. To
the reaction mixture was added 5.17 g (20.7 mmol) of 4-bromobenzyl bromide
at room temperature for 16 hours. To the reaction mixture at 0.degree. C.
was added a saturated aqueous solution of ammonium chloride followed by
extraction with ethyl acetate. The organic layer was washed with water and
concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with dichloromethane yielded 8.03 g (17.8 mmol) of
1-bromo-4-(2,5,8,11,14,16,19-heptaoxaeicosanyl)benzene.
To a solution of 8.03 g (17.8 mmol) of the above-obtained compound in dry
tetrahydrofuran (200 ml) was added 1.60M hexane solution of n-butyllithium
(16.7 ml, 26.7 mmol) in the atmosphere of argon at -78.degree. C. The
mixture was allowed to react for 30 min. To the solution was added 6.50 ml
(88.5 mmol) of acetone, and the mixture was reacted at -78.degree. C. for
10 min. To the reaction mixture was added a saturated aqueous solution of
ammonium chloride followed by extraction with ethyl acetate. The organic
layer was washed with water and concentrated under reduced pressure. The
residue thus obtained was subjected to silica gel column chromatography
for separation and purification. Elution with
dichloromethane-methanol(50:1) yielded 7.28 g (16.9 mmol) of
4-(2,5,8,11,14,16,19-heptaoxaeicosanyl)-1-(.alpha.-hydroxyisopropyl)benzen
e.
To 7.28 g (16.9 mmol) of the above-obtained hydroxy compound were added 20
ml of ether, 40 ml of 30% aqueous solution of hydrogen peroxide and 1.00
ml of concentrated sulfuric acid. The mixture was allowed to react at room
temperature for 15 hours followed by addition of water and extraction with
ethyl acetate. The organic layer was washed with water and concentrated
under reduced pressure. The residue thus obtained was subjected to silica
gel column chromatography for separation and purification. Elution with
ethyl acetate-hexane (2:1) yielded 5.36 g (12.0 mmol) of
4-(2,5,8,11,14,16,19-heptaoxaeicosanyl)cumene hydroperoxide.
NMR (ppm, CDCl.sub.3)
8.48(s, 1 H), 8.47-8.17(m, 4 H), 4.68(s, 2 H),
4.50(s, 2 H), 3.63 (s, 2 H), 3.35(s, 3 H), 1.57(s, 6 H) .
IR(.nu.cm.sup.-1,CHCl.sub.3) 3530, 3330.
EXAMPLE 3
Polyethylene glycol 4-(.alpha.-hydroperoxyisopropyl)benzyl methyl ether
##STR22##
To a solution of 1.63 g (40.8 mmol) of sodium hydride contained at 60% in
mineral oil in dry dimethylformamide (60 ml) was added in an atmosphere of
argon 4.94 g (6.59 mmol on average) of polyethylene glycol methyl ether
with an average molecular weight of 750, and the mixture was allowed to
react at 40.degree.-50.degree. C. for 30 min. To the reaction mixture was
added 2.47 g (9.88 mmol) of 4-bromobenzyl bromide, and the mixture was
allowed to react at room temperature for 16 hours. To the reaction mixture
at 0.degree. C. was added a saturated aqueous solution of ammonium
chloride followed by extraction with ethyl acetate. The organic layer was
washed with water and concentrated under reduced pressure. The residue
thus obtained was subjected to silica gel column chromatography for
separation and purification.
Elution with dichloromethane-methanol (50:1) yielded 3.81 g (4.15 mmol on
average) of a compound of the structure shown below.
##STR23##
To a solution of 3.81 g (4.15 mmol on average) of the above-obtained
compound in dry tetrahydrofuran (40 ml) was added 1.60M hexane solution of
n-butyllithium (3.90 ml, 6.24 mmol) in the atmosphere of argon at
-78.degree. C., and the mixture was allowed to react for 30 min. To the
solution was added 2.60 ml (35.4 mmol) of acetone, and the mixture was
allowed to react at -78.degree. C. for 10 min. To the reaction mixture was
added a saturated aqueous solution of ammonium chloride followed by
extraction with ethyl acetate. The organic layer was washed with water and
concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with dichloromethane-methanol (50:1) yielded 2.19 g
(2.48 mmol on average) of a compound of the structure shown below.
##STR24##
To 2.19 g (2.48 mmol on average) of the above-obtained hydroxy compound
were added 20 ml of ether, 40 ml of a 30% aqueous solution of hydrogen
peroxide and 1.00 ml of concentrated sulfuric acid. The mixture was
allowed to react at room temperature for 18 hours followed by addition of
water and extraction with ethyl acetate. The organic layer was washed with
water and concentrated under reduced pressure. The residue thus obtained
was subjected to silica gel column chromatography for separation and
purification. Elution with dichloromethane-methanol (25:1) yielded 1.06 g
(1.18 mmol on average) of the desired product.
NMR (ppm, CDCl.sub.3)
8.30(bs, 1 H), 7.47-7.10(m, 4 H), 4.50(s, 2 H),
3.63(s, 64 H), 3.33(s, 3 H), 1.48(s, 6 H).
IR(.nu.cm.sup.-1,CHCl.sub.3) 3530, 3330.
EXAMPLE 4
4-(8-Hydroxy-4-oxaoctyl)cumene hydroperoxide
##STR25##
To a solution of 1.00 g (10.2 mmol) of 1,4-butanediol in 20 ml of dry
dimethylformamide were added 2.80 g (10.2 mmol) of tert-butyldiphenylsilyl
chloride and 3.47 g (51.0 mmol) of imidazole in an atmosphere of argon.
The mixture was allowed to react at 0.degree. C. for 24 hours. To the
solution was added water followed by extraction with dichloromethane. The
organic layer was washed with water and concentrated under reduced
pressure. The residue thus obtained was subjected to silica gel column
chromatography for separation and purification. Elution with
dichloromethane-methanol (100:1) yielded 2.17 g (6.62 mmol) of
4-(tert-butyldiphenylsiloxy)-1-butanol.
To a solution of 2.17 g (6.62 mmol) of said compound in dry pyridine (48
ml) was added 1.39 g (7.29 mmol) of p-toluenesulfonyl chloride in the
atmosphere of argon. The mixture was allowed to react at room temperature
for 6 hours followed by addition of water and extraction with benzene. The
organic layer was washed with water and concentrated under reduced
pressure. The residue thus obtained was subjected to silica gel column
chromatography for separation and purification. Elution with
dichloromethane-hexane (1:2) yielded 2.94 g (6.10 mmol) of
4-(tert-butyldiphenylsiloxy)-1-(p-toluenesulfoxy)butane.
Next, to a solution of 405 mg (10.1 mmol) of sodium hydride contained at
60% in mineral oil in dry dimethylformamide (20 ml) was added 1.44 g (6.70
mmol) of 3-(4-bromophenyl)-1-propanol in the atmosphere of argon, and the
mixture was allowed to react at 100.degree. C. for 30 min. To the reaction
mixture was then added 2.94 g (6.10 mmol) of
4-(tert-butyldiphenylsiloxy)-1-(p-toluenesulfoxy)butane, and the mixture
was reacted at 100.degree. C. for 16 hours. To the reaction mixture at
0.degree. C. was added a saturated aqueous solution of ammonium chloride
followed by extraction with benzene. The organic layer was washed with
water and then concentrated under reduced pressure. The residue thus
obtained was subjected to silica gel column chromatography for separation
and purification. Elution with dichloromethane-hexane (1:4) yielded 1.29 g
(2.46 mmol) of 4-[8-(tert-butyldiphenylsiloxy)-4-oxaoctyl]-1-bromobenzene.
To a solution of 1.29 g (2.46 mmol) of the above-obtained compound in dry
tetrahydrofuran (50 ml) was added 1.60M hexane solution of n-butyllithium
(1.85 ml, 2.96 mmol) in the atmosphere of argon at -78.degree. C., and the
mixture was allowed to react for 30 min. To the solution was added 1.00 ml
(13.6 mmol) of acetone, and the mixture was reacted at -78.degree. C. for
10 min. followed by addition of saturated solution of ammonium chloride
and extraction with ethyl acetate. The organic layer was washed with water
and then concentrated under reduced pressure. The residue thus obtained
was subjected to silica gel column chromatography for separation and
purification. Elution with dichloromethane-methanol (100:1) yielded 898 mg
(1.84 mmol) of
4-[8-(tert-butyldiphenylsiloxy)-4-oxaoctyl]-1-(.alpha.-hydroxyisopropyl)-b
enzene.
To 898 mg (1.84 mmol) of the above-obtained hydroxy compound were added 5
ml of ether, 10 ml of a 30% aqueous solution of hydrogen peroxide and 0.25
ml of concentrated sulfuric acid. The mixture was allowed to react at room
temperature for 11 hours followed by addition of water and extraction with
ethyl acetate. The organic layer was washed with water and then
concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with ethyl acetate-hexane (1:2) yielded 853 mg (1.69
mmol) of 4-[8-(tert-butyldiphenylsiloxy)-4-oxaoctyl]cumene hydroperoxide.
Next, to a solution of 853 mg (1.69 mmol) of the above-obtained compound in
dry tetrahydrofuran (16 ml) was added a 1.0M tetrahydrofuran solution of
tetrabutylammonium fluoride (3.40 ml, 3.40 mmol) in the atmosphere of
argon, and the mixture was allowed to react at room temperature for 6
hours. To the solution was added water, and the mixture was extracted with
ethyl acetate. The organic layer was washed with water and then
concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with dichloromethane-methanol yielded 428 mg (1.52
mmol) of 4-(8-hydroxy-4-oxaoctyl)cumene hydroperoxide.
NMR (ppm, CDCl.sub.3)
8 03(s, 1 H), 7.38-7.04(m, 4 H), 3.52-3.16
(m, 6 H), 2.56-2.23(m, 2 H), 2.06-1.77(m, 6 H),
1.56(s, 6 H).
IR(.nu.cm.sup.-1,CHCl.sub.3) 3610, 3530, 3400.
EXAMPLE 5
3-(1,1-Dimethyl-2,4,7-trioxaoctyl)cumene hydroperoxide
##STR26##
To a solution of 3.34 g (16.8 mmol) of 3'-bromoacetophenone in dry diethyl
ether (68 ml) was added 1.4M diethyl ether solution of methyllithium (18.0
ml, 25.2 mmol) in an atmosphere of argon at 0.degree. C., and the mixture
was allowed to react for 30 min. To the solution was added a saturated
aqueous solution of ammonium chloride, and the mixture was extracted with
ethyl acetate. The organic layer was washed with water and then
concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with dichloromethane-methanol yielded 3.47 g (16.1
mmol) of 3-(.alpha.-hydroxyisopropyl)-1-bromobenzene.
To a solution of 3.47 g (16.1 mmol) of the above-obtained compound in dry
dichloromethane (35 ml) were added in the atmosphere of argon 2.20 ml
(19.3 mmol) .beta.-methoxyethoxy methyl chloride and 4.20 ml (24.1 mmol)
of N,N-diisopropylethylamine, and the mixture was refluxed for 16 hours.
To the solution was added water, and the mixture was extracted with
dichloromethane. The organic layer was washed with water and concentrated
under reduced pressure. The residue thus obtained was subjected to silica
gel column chromatography for separation and purification. Elution with
dichloromethane yielded 4.34 g (14.3 mmol) of
3-(1,1-dimethyl-2,4,7-trioxaoctyl)-1-bromobenzene.
To a solution of 4.34 g (14.3 mmol) of the above-obtained compound in dry
tetrahydrofuran (160 ml) was added 1.60M hexane solution of n-butyllithium
(13.4 ml, 21.4 mmol) in the atmosphere of argon at -78.degree. C., and the
mixture was allowed to react for 30 min. To the solution was added 5.30 ml
(72.2 mmol) of acetone, and the mixture was reacted -78.degree. C. for 10
min. followed by addition of a saturated aqueous solution of ammonium
chloride and extraction with ethyl acetate. The organic layer was washed
with water and then concentrated under reduced pressure. The residue thus
obtained was subjected to silica gel column chromatography for separation
and purification. Elution with dichloromethane-methanol (50:1) yielded
3.51 g (12.4 mmol) of
3-(1,1-dimethyl-2,4,7-trioxaoctyl)-1-(.alpha.-hydroxyisopropyl)-benzene.
To 3.51 g (12.4 mmol) of the above-obtained hydroxy compound were added 20
ml of ether, 40 ml of a 30% aqueous solution of hydrogen peroxide and 1.00
ml of concentrated sulfuric acid, and the mixture was allowed to react at
room temperature for 14 hours followed by addition of water and extraction
with ethyl acetate. The organic layer was washed with water and then
concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with ethyl acetate-hexane (1:1) yielded 3.07 g (10.3
mmol) of 3-(1,1-dimethyl-2,4,7-trioxaoctyl)cumene hydroperoxide.
NMR (ppm, CDCl.sub.3)
8.20(s, 1 H), 7.55-7.23(m, 4 H), 4.71(s, 2 H),
3.85-3.31(m, 4 H), 3.33(s, 3 H), 1.95(s, 6 H),
1.55(s, 6 H).
IR(.nu.cm.sup.-1,CHCl.sub.3) 3530, 3320.
EXAMPLE 6
4-(.alpha.-Hydroperoxyisopropyl)benzyl benzyl ether
##STR27##
To a solution of 1.07 g (26.8 mmol) of sodium hydride contained at 60% in
mineral oil in dry dimethylformamide (80 ml) was added 4.02 g (21.5 mmol)
of benzyl alcohol in an atmosphere of argon, and the mixture was allowed
to react at 40.degree.-50.degree. C. for 30 min. To the reaction mixture
was then added 4.47 g (17.9 mmol) of 4-bromobenzyl bromide, and the
mixture was allowed to react at room temperature for 19 hours. To the
reaction mixture at 0.degree. C. was added a saturated aqueous solution of
ammonium chloride, and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and then concentrated under reduced
pressure. The residue thus obtained was subjected to silica gel column
chromatography for separation and purification. Elution with
dichloromethane-hexane (1:2) yielded 4.61 g (16.6 mmol) of 4-bromophenyl
benzyl ether.
To a solution of 4.61 g (16.6 mmol) of the above-obtained compound in dry
tetrahydrofuran (100 ml) was added 1.21 g (49.8 mmol) of magnesium in the
atmosphere of argon, and the mixture was allowed to react at room
temperature for 2 hours. To the solution was added 7.50 ml (102 mmol) of
acetone, and the mixture was reacted at 0.degree. C. for 10 min. followed
by addition of a saturated aqueous solution of ammonium chloride and
extraction with ethyl acetate. The organic layer was washed with water and
then concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with dichloromethane-methanol (100:1) yielded 3.45 g
(13.5 mmol) of 4-(.alpha.-hydroxyisopropyl)-benzyl benzyl ether.
To 3.45 g (13.5 mmol) of the above-obtained hydroxy compound were added 10
ml of ether, 20 ml of a 30% aqueous solution of hydrogen peroxide and 0.50
ml of concentrated sulfuric acid. The mixture was allowed to react at room
temperature for 14 hours followed by addition of water and extraction with
ethyl acetate. The organic layer was washed with water and then
concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with ethyl acetate-hexane (1:2) yielded 3.23 g (11.9
mmol) of 4-(.alpha.-hydroperoxyisopropyl)benzyl benzyl ether.
NMR (ppm, CDCl.sub.3)
8.23(bs, 1 H), 7.52-7.20(m, 9 H), 4.52(s, 4 H),
5 1.57(s, 6 H).
IR(.nu.cm.sup.-1,CHCl.sub.3) 3530, 3320.
EXAMPLE 7
4-(.alpha.-Hydroperoxyisopropyl)benzyl 4-nitrobenzyl ether
##STR28##
To a solution of 812 mg (20.3 mmol) of sodium hydride contained at 60% in
mineral oil in dry dimethylformamide (100 ml) was added 3.01 g (16.1 mmol)
of 4-bromobenzyl alcohol in the atmosphere of argon, and the mixture was
allowed to react at 40.degree.-50.degree. C. for 30 min. followed by
addition of 2.85 g (13.2 mmol) of 4-nitrobenzyl bromide. The mixture was
reacted at room temperature for 17 hours. To the reaction mixture at
0.degree. C. was added saturated aqueous solution of ammonium chloride
followed by extraction with ethyl acetate. The organic layer was washed
with water and then concentrated under reduced pressure. The residue thus
obtained was subjected to silica gel column chromatography for separation
and purification. Elution with dichloromethane-hexane (1:1) yielded 2.76 g
(8.57 mmol) of 4-bromobenzyl 4-nitrobenzyl ether.
To a solution of 2.76 g (8.57 mmol) of the above-mentioned compound in dry
tetrahydrofuran (90 ml) at -78.degree. C. was added 1.60M hexane solution
of n-butyllithium (6.43 ml, 10.3 mmol), and the mixture was allowed to
react for 30 min. To the resulting solution was added 3.20 ml (43.6 mmol)
of acetone, and the mixture was allowed to react at -78.degree. C. for 10
min. To the reaction mixture was added a saturated aqueous solution of
ammonium chloride followed by extraction with ethyl acetate. The organic
layer was washed with water and then concentrated under reduced pressure.
The residue thus obtained was subjected to silica gel column
chromatography for separation and purification. Elution with
dichloromethane-methanol (50:1) yielded 1.37 g (4.55 mmol) of
4-(.alpha.-hydroxyisopropyl)benzyl 4-nitrobenzyl ether.
To 1.37 g (4.55 mmol) of the above-obtained hydroxy compound were added 10
ml of ether, 20 ml of a 30% aqueous solution of hydrogen peroxide and 0.50
ml of concentrated sulfuric acid. The mixture was allowed to react at room
temperature for 16 hours followed by addition of water and extraction with
ethyl acetate. The organic layer was washed with water and then
concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with ethyl acetate-hexane (1:1) yielded 1.01 g (3.19
mmol) of 4-(.alpha.-Hydroperoxyisopropyl)benzyl 4-nitrobenzyl ether.
NMR (ppm, CDCl.sub.3)
8.23(s, 1 H), 8.06(d, 2 H, J=7 Hz), 7.55-7.23(m, 6 H), 4,78(s, 2 H),
4.55(s, 2 H), 1.53(s, 6 H).
IR(.nu.cm.sup.-1, CHCl.sub.3) 3530, 3330.
EXAMPLE 8
4-(.alpha.-Hydroperoxyisopropyl)benzyl 3,4,5-trimethoxyphenyl ether
##STR29##
To a solution of 1.46 g (36.5 mmol) of sodium hydride contained at 60% in
mineral oil in dry dimethylformamide (50 ml) was added 2.02 g (11.0 mmol)
of 3,4,5-trimethoxyphenol in an atmosphere of argon, and the mixture was
allowed to react at 0.degree. C. for 15 min. To the reaction mixture was
added 3.60 g (14.4 mmol) of 4-bromobenzyl bromide. The resulting mixture
was reacted at room temperature for 24 hours. To the reaction mixture at
0.degree. C. was added a saturated aqueous solution of ammonium chloride
followed by extraction with ethyl acetate. The organic layer was washed
with water and then concentrated under reduced pressure. The residue thus
obtained was subjected to silica gel column chromatography for separation
and purification. Elution with dichloromethane-hexane (1:1) yielded 3.28 g
(9.28 mmol) of 4-bromobenzyl 3,4,5-trimethoxyphenyl ether.
To a solution of 3.28 g (9.28 mmol) of the above-obtained compound in dry
tetrahydrofuran (120 ml) at -78.degree. C. was added 1.60M hexane solution
of n-butyllithium (8.70 ml, 13.9 mmol) in the atmosphere of argon, and the
mixture was allowed to react for 30 min. To the solution was added 3.40 ml
(46.3 mmol) of acetone, and the mixture was reacted at -78.degree. C. for
10 min. To the reaction mixture was added a saturated aqueous solution of
ammonium chloride followed by extraction with ethyl acetate. The organic
layer was washed with water and then concentrated under reduced pressure.
The residue thus obtained was subjected to silica gel column
chromatography for separation and purification. Elution with ethyl
acetate-hexane (1:3) yielded 1.72 g (5.17 mmol) of
4-(.alpha.-hydroxyisopropyl)benzyl 3,4,5-trimethoxyphenylether.
To 1.72 g (5.17 mmol) of the above-obtained hydroxy compound were added 10
ml of ether, 20 ml of a 30% aqueous solution of hydrogen peroxide and
0.500 ml of concentrated sulfuric acid. The mixture was allowed to react
at room temperature for 15 hours followed by addition of water and
extraction with ethyl acetate. The organic layer was washed with water and
then concentrated under reduced pressure. The residue thus obtained was
subjected to silica gel column chromatography for separation and
purification. Elution with ethyl acetate-hexane (1:1) yielded 1.48 g (4.25
mmol) of 4-(.alpha.-hydroxyisopropyl)benzyl 3,4,5-trimethoxyphenyl ether.
NMR (ppm, CDCl.sub.3)
8.67(bs, 1 H), 7.53-7.27(m, 4 H), 4.95(s, 2 H),
3.77(s, 9 H), 1.57(s, 3 H).
IR(.nu.cm.sup.-1,CHCl.sub.3) 3530, 3330.
EXAMPLE 9
Polyethylene glycol 4-(.alpha.-hydroperoxyisopropyl)benzyl
4-(1,3-dimethylbutyl)phenyl ether
##STR30##
To a solution of 2.14 g (53.4 mmol) of | | |
