Note: Descriptions are shown in the official language in which they were submitted.
PECIFICATION
A PROCESS FOR PRODUCING A PARA-SUBSTITUTED PHENOL
DERIVATIVE
FIELD OF THE INVENTION
This invention relates to a process for producing
a para-substituted phenol derivativeO More particularly,
the present invention is concerned with a process for
producing a para-substituted phenol derivative which
comprises reacting a phenol compound with an organic
halide selected from the group consisting of a haloform,
a carbon tetrahalide and a substituted or unsubstituted
allyl halide in the presence of an alkali metal hydroxide,
using as a catalyst a fixed cyclodextrin having hydroxyl
groups crosslinked with a bivalent hydrocarbon group
having free valences at its both ends.
DES~RIPTIGN OF T~E PRIOR ART
It is known that 2,5-cycloh~xadienone derivatives
having a dihalomethyl group at the 4-position, 2,5-
cyclohe~adienone derivatives having a substituted orunsubstituted allyl group at the 4-position, para-
hydroxybenzoic acid derivatives, or para-hydroxybenzaldehyde
derivatives are prepared by reacting a phenol with a
haloform under al~aline conditions. The products thus
obtained are extremely valuable compounds as pharma-
ceuticals, agricultural chemicals, or raw materials ~or
, ,~
~343~3
polymers, various physiologically active substances
such as agricultural chemicals and pharmaceuticals, and
dyes.
However, known reaction processes have serious
disadvantages or extremely low selectivity and therefore
poor yield. Accordingly, the known processes cannot be
advantageously used in practice.
For example, para-hydroxybenzaldehyde which,
nowadays, is of increasing importance as an anticarcinogen
or a raw material for pharmaceuticals, agricultural
chemicals and dyes, has conventionally been synthesized
by reacting phenol with chloroform in the presence of
an alkali. In the reaction, however, para-hydroxybenzalde-
hyde is obtained in a selectivity as low as about 30%,
and a large amount of salicylaldehyde is formed as a by-
product. Therefore, the production of para-hydroxy
benzaldehyde in accordance with this process requires
not only a large amount of raw materials but also a
complicated operation for separation.
2,4-Dihydroxybenzaldehyde, nowadays, is also of
increasing importance in view of its interesting
behaviors such as cancer-controlling effect, plant root
growth-promoting effect, antibacterial effect and
photophosphorylation-controlling effect in chloroplast.
For the production of 2,4-dihydroxybenzaldehyde, known
is a process in which 1,3-dihydro~ybenzene is reacted
3~393
with chloroform in the presence of an alkali. However,
in this known process, a large amount of 2,4-dihydroxy-3-
formylbenzaldehyde is formed as a by-product, and 2,4-
dihydroxybenzaldehyde which is the intended product is
obtained only in low yield and with low selectivity.
Accordingly, for producing 2,4-dihydroxybenzaldehyde by
this process, not only large amounts of raw materials
but also a complicated operation for separation is
required.
As to the production of para-hydroxybenzoic acid
which, nowadays, is of increasing importance as a raw
material for heat resistant polymers, agricultural
chemicals and pharmaceuticals, known is the Kolbe-Schmitt
reaction in which para-hydroxybenzoic acid is synthesized
by treating phenol with potassium hydroxide and potassium
carbonate, followed by heating together with carbon
dioxide under pressure. The reaction, however, has
disadvantages that a costly pressure resistant apparatus
is required because of high pressure applied during the
2~ reaction, and that much energy is required for the
achievement a highly anhydrous condition which is
indispensable to the reaction. Also known is another
process in which phenol is reacted with carbon tetrachloride
in the presence of an alkali to prepare para-hydroxybenzoic
acid. In the process, however, the selectivity for the
formation of para-hydroxybenzoic acid is 57 ~, and the
3~3
reaction gives a large amount of salicylic acid as a
by-product. Therefore, the process also requires not
only large amounts of raw materials but also a
complicated operation for separation.
~ 2,5-Cyclohexadienone derivatives having an allyl
group at the 4-position are also highly reactive due to
the conjugation of two C-C double bonds and a carbonyl
group, and therefore, are valuable as raw materials for
the syntheses of physiologically active substances and
other useful substances. Moreover, many of 2, 5-
cyclohexadienone derivatives themselves have physiological
activities. Hitherto is known the Reimer-Tiemann
reaction in which a para-substituted phenol is reacted
with a haloform and sodium hydroxide or potassium
hydroxide to give a 4-dihalomethyl-2,5-cyclohexadienone
derivative. The reaction, however, gives as major
product a compound having a substituent introduced
mainly to the ortho-position. Therefore, the conventional
process gives 2,5-cyclohexadienone derivatives in a yield
as low as 5 to 10 %, and requires not only large amounts
of raw materials but also a complicated operation for
separation.
2,5-Cyclohexadienone derivatives having an allyl
group at the 4-position are also highly reactive due to
the conjugation of two C-C double bonds and a carbonyl
group. In addition, they have an allyl group at such a
-- 4 --
~ '`'' ` ,
393
position that an intramolecular ring-forming reaction
is readily caused to occur. Accordingly, the derivatives
are valuable compounds as starting materials for
preparing physiologically active substances and other
useful substances. 2,5-Cyclohexadienone derivatives
having an allyl group at the 4-position have conventionally
been prepared by a process comprising two steps, namely,
the first step in which a 1:1 mixture of sodium methoxide
and a para-substituted phenol is reacted with an allyl
halide in an aromatic solvent to produce a ~,4-cyclo-
hexadienone derivative which is allyl-substituted at the
6-position, and the second step in which the product in
the first step is then reacted in a methanol-hydrochloric
acid mixture to allow the allyl group to transfer to the
4-positionO The process, however, has disadvantages
that the 2,4-cyclohexadienone derivative which is a
reaction product o~ the first step is difficult to
separate and purify, and that the reactions involved in
the process require large amounts of organic solvents.
The present inventors have previously found that,
when a phenol compound is reacted with an organic halide
in the presence of cyclodextrin under an alXaline
condition, a substituent group derived from said organic
halide is introduced to the 4-position of the phenol
compound with high selectivity, and, therefore, the
i~tended para-substituted phenol derivative can be
~343~3
obtained in high yield (European Patent Application
Laid-Open Specification No. 0073837). However, as well
known, cyclode~trin is soluble in an alkaline aqueous
solution, and therefore, for recovering the cyclodextrin
after completion of the reaction, it is required to
acidify the reaction system by adding an acid thereto to
deposite and separate the cyclodextrin therefrom. Such
an operation for recovering the cyclodextrin is not only
troublesome but also has a disadvantage that 10 to 20
of the cyclodextrin employed for the reaction is
usually lost during the step of recovery. Accordingly,
since cyclodextrin is highly expensive, the process
is extremely disadvantageous in manufacturing the
above-mentioned various valuable substances and inter-
mediates thereof by reacting phenols with organic
halides on a commercial scale.
On the other hand, hydroxychalcone and its
derivatives, nowaday, are of increasing importance as
a remedy for gastrointestinal ulcers and tumors, as an
anti-inflammatory agent, and as an inter~.ediate for preparing
a variety of pharmaceuticals, and agricultural chemicals.
It is already known that 4-hydroxychalcone and its
derivatives are prepared by reacting phenol with a
haloform in the presence of an alkali to give 4-hydroxy-
benzaldehyde and reacting the obtained 4-hydroxybenzalde-
hyde with acetophenone or its derivative. It is also
g3
known that 4-hydroxy-3-carboxychalcone derivatives are
prepared by reacting 4-hydroxybenzaldhyde with a carbon
tetrahalide in the presence of an alkali to give 2-
hydroxy-5 formylbenzoic acid and then reacting the
obtained 2-hydroxy-5-formylbenzoic acid with acetophenone
and its derivatives. However, when the above-mentioned
processes are practiced, not only the intended products
are obtained only in low yields but also large amounts
of by-products are unfavorably produced. Therefore,
the above-mentioned processes are impractical.
As described above, any of the conventional
processes for preparing para-substituted phenol
derivatives are unsatisfactory from a practical point
of view because of e~tremely low selectivity, necessity
of complicated steps for recovering the catalyst
employed and much loss of catalyst. The elimination
of the disadvantages accompanying conventional processes
has been strongly desired.
DISC~OSURE OF THE PRESENT INVENTION
The present inventors have made e~tensive and
intensive studies to develop a process for preparing
para-substituted phenol derivatives, in which not only
para-substituted phenol derivatives can be obtained in
high yield and with high selectivity but also the catalyst
is not lost and can be recovered easily from the reaction
-- 7 --
~Z;3~3~3
mixture. As a result, the present inventOrS have
surprisingly found that the disadvantages of the
conventional processes can be eliminated by using as a
catalyst a fixed cyclodextrin having hydroxyl groups
crosslinked with a bivalent hydrocarbon group having
free valences at its both ends and that the para-
substituted phenol derivatives can be prepared extremely
advantageously from a practical point of view.
Specifically, the present inventors have found that, by
employing the above-mentioned fixed cyclodex~rin as a catalyst,
the intended para-substituted phenol derivatives can be
prepared in high yield and with high selectivity (of
which the definition will be given later) and that since
the fixed cyclodextrin is insoluble in the reaction system
the employed fixed cyclodextrin can be recovered with
great ease from the reaction mixture, for example, by
centrifugation and filtration. Further, it has been
surprisingly found that even when the recovered fixed
cyclodextrin is repeatedly employed as a catalyst the
para-substituted phenol derivatives can be prepared
without lowering in yield and selectivity. Based on
such novel findings, the present invention has been made.
According to the present invention, there is
provided a process for producing a para-substituted phenol
deriva~ive which comprises reacting a phenol compound
represented by the formula (I)
-- 8 --
, -
39~
OH
C ~ D (I)
B~ ~ E
wherein A, B, C, D and E each independently stand
for hydrogen, a hydroxyl group, a carboxyl group,
a sulfonic group, a halogen atom, a substituted or
unsubstituted alkyl group, a substituted or un-
substituted allyl group, a substituted or unsub-
stituted alkoxyl group or a substituted or unsub-
stituted aryl group, provided that ~ does not stand
for a hydroxyl group, a carboxyl group and a sulfonic
group and that when two or more of A, B, C, D, and E
each independently stand for a substituted or
unsubstituted alkyl group or a substituted or
unsubstituted alkoxyl gruoup, they have their
respective free terminal ends or at least one of
them is bonded to another group selected from said
alkyl and alkoxyl groups to form a ring,
with an organic halide selected from the group consisting
of a haloform, a carbon tetrahalide and a substituted or
unsubstituted allyl halide in the presence of an alkali
metal hydroxide, using as a catalyst a fixed cyclodextrin
having hydroxyI groups crosslinked with a bivalent
hydrocarbon group having free valences at its both ends,
said hydrocarbon group having at least one hydrogen atom
~3~3~3
substituted or unsubstituted with a member selected from
the group consisting of an alkyl group, a halogen atom
and a hydroxyl group and containing or not containing
at least one combination of two neighboring carbon atoms
having therebetween at least one member selected from the
group consisting of an oxygen atom, a sulfur atom and
phenylene, thereby to obtain a reaction mixture contain-
ing a para-substituted phenol derivative; and
(2) isolating the para-substituted phenol
derivative from said reaction mixture.
By the term "phenol compound" as used herein is
meant phenol (hydroxybenzene) or its derivative which is
defined by the above-mentioned formula (I). The substi-
tuted or unsubstituted alkyl group, the substituted or
unsubstituted allyl group, the substituted or unsubsti-
tuted alkoxyl group and the substituted or unsubstituted
aryl group each may preferably have carbon atoms of not
more than 6.with respect to the substituents B, C, D and
.
E, and each may preferably have carbon atoms of not more
than 12 with respect to the substituent A.
The organic halide which is one of the reactants to
be used in the process of the present invention is
selected from the group consisting of a haloform, a
carbon tetrahalide and a substituted or unsubstituted
allyl halide. The substituted or unsubstituted allyl
halide may preferably have carbon atoms of not more
-- 10 --
3~
than 12. As such an allyl halide, the chloride and
bromide are especially preferred. The organic halide
may be used in an amount of 1 to 20 mols, preferably 1.5
to 10 mols per mol of the phenol compound used.
The alkali metal hydroxide to be used in the
process of the present invention may preferably be
sodium hydroxide or potassium hydroxide. The alkali
metal hydroxide may be used in a stoichiometrical amount
relative to the phenol compound. Usually, however, 1 to
lS times, preferably 1.5 to 10 times the stoichiometrical
amount of the alkali metal hydroxide may be used taking
into consideration of the rate of reaction and the like.
The reaction according to the process of the
present invention is usually carried out in a reaction
medium As the reaction medium, there is employed an
aqueous solvent, preferahly water, because of the
requirement tha~ the reaction medium be capable of
dissolving the alkali metal hydroxide therein. There
may also be used, as the reaction medium, a mixture of
water with a small amount of an organic solvent which
is soluble in water and can be present stably under the
reaction conditions. Examples of such an organic
solvent include methanol, ethanol, acetone, dimethoxyethane
and the like. The concentration of ~he alkali metal
hydroxide in the reaction solvent may be in the range of
0.1 to 50 ~ by weight. The preferred concentration of
-- 11 --
:L~3~L3~33
the alkali metal halide in the reaction medium varies
depending on the kind of the organic halide to be
employed. Specifically, where the organic halide is a
haloform, the range of concentration is preferably 5 to
20 ~ by weight, more preferably lO to 15 ~ by weight.
Where the organic halide is a car~on tetrahalide or an
allyl halide, the range of concentration is preferably
0.1 to 30 % by weight, more preferably 0.5 to 25 % by
weight. ~hen acetophenone or its derivative is added
to the reaction mixture obtained by the reaction of
organic halide with a phenol compound to give a hydroxy-
chalcone compound, the concentration of the alkali metal
hydroxide in the reaction medium is preferably 5 to 20
by weight.
The fixed cyclodextrin to be used in the process
of the present invention is a granular solid or a gel,
ar.d the cyclodextrin has hydroxyl groups crosslinked
with a bivalent hydrocarbon group having free valences at
. ~ .
its both ends. The fixed cyclodextrin is insoluble in
the reaction system and remains unchanged chemically
during the reaction. The hydrocarbon group may have
at least one hydrogen atom substituted with a member
selected from the group consisting of an alkyl group, a
halogen atom such as fluorine and chlorine, and a
hydroxyl group. In this case, an alkyl group having 6
or less carbon atoms is preferred. As the preferable
~.~3~3~
number of substituents, there may be mentioned ~ or
less in the case of an alkyl group, 20 or less in the
case of a halogen atom, and 10 or less in the case of
a hydroxyl group. Moreover, the hydrocarbon group may
contain at least one combination of two neighboring
carbon atoms having therebetween at least one member
selected from the group consisting of an oxygen atom,
a sulfur atom and a phenylene. In this case, the
number of oxygen atoms, sulfur atoms and phenylenes
contained in the hydrocarbon group are preferably 8 or
less, 8 or less and 2 or less, respectively. In general,
the hydrocarbon group contains preferably 2 to 20 carbon
atoms, more preferably 2 to 10 carbon atoms.
As specific examples of the hydrocarbon group, there
may be mentioned groups represented by the following
general formulae. But the hydrocarbon group is not
limited to the groups represented by the following
general formulae.
Rl
-CH2-CHtCtnl - (IV)
OH R2
wherein nl is an integer from 1 to 10, and Rl and
R2 each independently stand for a hydrogen atom,a
halogen atom, a hydroxyl group or an alkyl group
having 6 or less carbon atoms;
- 13 -
~: " ' ,,.
:3123~393
R3RS
-CH2-CE-CH2 ~ )n2 CH2 1 2
OH R4R6 OH
wherein n2 is an integer from 1 to 6, and R3, R4,
R5 and R6 each independently stand for a hydrogen
atom, a halogen atom, a hydroxyl group or an alkyl
group having 6 or less carbon atoms;
R7R9
2 FH CE2 -~-1~l~S)n3 CH2-CH-CH2- (VI)
OH R8R10 OH
wherein n3 is an integer from 1 to 6, and R , R8,
R9 and R10 each independently stand for a hydrogen
atom, a halogen atom, a hydroxyl group or an alkyl
group having 6 or less carbon atoms; and
2 fH CH2 O ( ~ _ O) 4 CH2-fH-CH2- (VII)
OH OH
wherein n4 is an integer from 1 to 2.
The preferable numbers of halogen atoms, hydroxyl groups
and alkyl groups contained in the hydrocarbon group
represented by the formulae given above are 20 or less,
10 or less and 4 or less, respectively.
As preferable examples of the hydrocar~on group
there may be mentioned 2-hydroxypropylene, 2-hydroxybutylene,
::
- 14 -
.. ,
:. .
~3~3~
2-hydroxypentylene, 2,9-dihydroxy-4,7-dioxadecylene, 2,10-
dihydroxy-4,8-dioxaundecylene, and 2,11-dihydroxy-4,9-
dioxadodecylene. of them,2-hydroxypropylene and 2,g-
dihydroxy-4,7-dioxadecylene are more preferred.
As the cyclodextrin to be crosslinked with the
bivalent hydrocarbon group having free valences at its
both ends, there may be mentioned a modified or
unmodified ~ - or y-cyclodextrin. A preferable kind of
cyclodextrin varies according to the kind of the organic
halide to be used.
Specifically, where the organic halide is a haloform,
~-cyclodextrin and ~-cyclodextrin are preferred, and ~-
cyclodextrin is more preferred. Where the organic halide
is a carbon tetrahalide, B-cyclodextrin is preferred.
Where the organic halide is an allyl halide, ~-cyclodextrin
and ~-cyclodextrin are preferred, and ~-cyclodextrin is
more preferred. When a modified cyclodextrin is used
as the cyclodextrin, there may be employed a modified
~ or r-cyclodextrin of which the primary hydroxyl
groups are all or partly substituted, for examplet with
a methoxy group. When an allyl halide is used as the
organic halide, a fixed modified ~-cyclodextrin is
particularly preferred. Incidentally, the modified
cyclodextrin may be prepared according to the method
descri~ed in Helv. Chim. Acta, 61, 2190 (197~).
3~ 33
The fi~ed cyclodextrin in which a modified or
unmodified cyclodextrin has hydroxyl groups crosslinked
can be obtained by reacting the cyclodextrin with a
crosslinking agent in the presence of an alkali metal
hydroxide such as potassium hydroxide and sodium
hydroxide. As the crosslinking agent, there may be
employed crosslinking agents represented by the formulae
(IV'), (V'), (VI') and (VII') which respectively
correspond to the hydrocarbon groups represented by the
above-described formulae (IV), (V), (VI) and (VII).
Rll
CH2-~CH~ )nl (IV~)
O R2
wherein X stands for a halogen atom, preferably a
chlorine atom or a bromine atom, and nl, Rl and R2
are as derined above;
- R3R5
. CH2-CH-cH2-O-t-c-c-o)n2 CH2 C\ /CH2 (V')
wherein n2, R3, R4, R5 and R6 are as defined above;
R7R9
C~2-CH-CH2-0--t--lC-lC-S) 3 CH2-C~-CH2 (VI')
O R8RlO o
wherein n3, R7, R8, R9 and RlO are as defined
above;. and
16 -
~ ..,
~343~3
CH2-CH-CH2-O ( ~ _o) 4 CH2-C\ /H2 (VII')
wherein n4 is as defined above.
In view of availability and ease in handling and
catalytic performance of the resulting fixed cyclodextrin,
epichlorohydrin, epibromohydrin and ethylene glycol
diglycydyl ether are preferably employed as the cross-
linking agent.
The molar ratio of the crosslinking agent to
cyclodextrin in the reaction for crosslinking is
preferably 1.0 to 30, and the molar ratio of the alkali
metal hydroxide to th~ crosslin~ing agent is preferably
in the range of 1.0 to 2Ø The crosslinking reaction
can be carried out in the presence of both of an alkali
metal hydroxide and sodium borohydride. In this case,
the molar ratio of sodium Doronydride to ~he crosslinking
agent is preferably in the range of 0.001 to 0.1. The
reaction is generally effected at a temperature of 40
to 90C. The reaction time is not critical, but is
generally 10 minutes to 4 hours.
The cyclodextrin content o-f the fixed cyclodextrin
employed in the process of the present invention is
preferably in the range of 20 to 96 % by weight, more
preferably in the range of 40 to 96 %. The cyclodextrin
content of the fixed cyclodextrin can easily be adjusted
,
- 17 -
1, , .............................................................. ~
,
by varying the kind of the crosslinking agent~ the
molar ratio of -the crosslinking agent to cyclodextrin
or the like. When the fixed cyclodextrin is granular
solid, the cyclodextrin content may be determined by
means of elementary analysis. When the fixed cyclodextrin
is a gel, the cyclodextrin content may be determined by
means of lH-NMR.
In the process of the present invention, the molar
ratio of the fixed cyclodextrin on the basis of
cyclodextrin in the fixed cyclodextrin (hereinafter
often referred to simply as "fixed cyclodextrin") to the
organic halide is preferably 0.001 to 20. A more
preferable range of the ratio of the fixed cyclode~trin
to the organic halide varies depending on the kind of the
organic halide to be used. Specifically, where the
organic halide is a haloform, the molar ratio of the
fixed cyclodextrin to the organic halide is preferably
0.5 to lO, more preferably 0.8 to 5. Where the organic
halide is a carbon tetrahalide, the molar ratio of the
fixed cyclodextrin to the carbon tetrahalide is preferably
0.001 to 5. Where the organic halide is an allyl halide,
the molar ratio of the fixed cyclodextrin to the allyl halide
is preferably 0.01 to lO, more preferably 0.1 to 5.
In practicing the process of the present invention,
all the amount of the organic halide to be used may be
added to a solution containing a phenol compound, an
- 18 -
.. . .
~34~93
alkali metal hydroxide and a fixed cyclodextrin at the
time of initiation of the reaction. A~ternatively,
the organic halide may be added to a system comprising
a phenol compound, an alkali metal hydroxide and a
fixed cyclodextrin so that the molar ratio of the fixed
cyclodextrin to the organic halide is maintained at a
value falling within the range as mentioned above.
The latter mode of process can be practiced by inter-
mittently or gradually adding the organic halide to the
above-mentioned system. In this mode of process, the
para substituted phenol derivatives can be obtained at
a high selectivity even by the use of a small amount of
the fixed cyclodextrin, leading to economical advantages.
In this case, the control of the molar ratio of the
fixed cyclodextrin to the organic halide in the reaction
syst,em may be made by the following method. During
the course of the reaction, at predetermined time
intervals, part of the reaction mixture is taken,
subjected to the determination of the organic halide
contained therein by gas chromatography, and the rate
of addition of the organic halide to the reaction
system is adjusted so that the molar ratio of the fixed
cyclodextrin to the organic halide is maintained at a
value falling within the range as mentioned above.
2S In the process of the present invention, in general,
the fixed cyclodextrin may be used in an amount of
-- 19 --
;
. . ~.
~ ~3~3~3
0.00001 to 10 in terms of molar ratio with respect to
the phenol compound used. A preferable molar ratio of
the cyclodextrln to the phenol compound ~aries depending
on the kind of the organic halide to be used. Specifi-
cally, where the organic halide is a haloform, the molar
ratio of the fixed cyclodextrin to the phenol compound
is preferably 0.00001 to 5, more preferably 0.01 to 5,
particularly preferably 0.5 to 5. Where the organic
halide is a carbon tetrahalide, the molar ratio of the
cyclodextrin to th~ phenol compound is preferably 0.001
to 10, more preferably 0.001 to 1, particularly
preferably 0.01 to 0.5. Where the organic halide is
an allyl halide, the molar ratio of the fixed cyclodextrin
to the allyl halide is preferably 0.0001 to 10, more
preferably 0.01 to 10, particularly preferably 0.1 to 5.
The reaction temperature is not critical, and may
be suitably determined according to a phenol compound to
be used, but generally is 0 to 120C, preferably 20 to
100C.
The reaction time is also not critical, and may be
suitably determined according to the kinds of a phenol
compound and an organic halide to be used, the amounts
of reactants, reaction temperature, manner of addition
of reactants and the like but generally is 10 minutes
to 40 hours.
- 20 -
~ A _
3~3
The reaction pressure is also not restricted, and
the reaction is usually carried out at atmospheric
pressure from a viewpoint of ease in operation.
By the reaction of the phenol compound with the
organic halide according to the process of the present
invention, there'is produced a para-substituted phenol
derivative of the kind corresponding to the kinds
of the phenol compound and the organic halide, as
described later.
10 Fron~ phenol compounds of the formula(I) in which A
is a hydrogen atom, para-hydroxybenzaldehydes, para-
hydroxybenzoic acids or para-allyl phenols are obtained.
From phenol compounds of the formula(I) in which ~
is a substituent other ~ n hydrogen, namely, a substituted
or unsubstituted alkyl group, a substituted or unsubsti-
tuted allyl group, substituted or unsubstituted alkoxyl
group or substituted or unsubstituted aryl group, there
is obtained 4-dihalomethyl-2,5-cyclohexadienone
derivatives or 4-allyl-2,5-cyclohexadienone derivatives
are obtained. Specifically, when A in the formula(I)
is hydrogen, there is obtained a para-substituted
phenol deviative represented by the formula(II)
OH
C ~ D
1 il (II)
E
~ 21 -
,
! ' _ ` ' .
~3~393
wherein s, C, D and E are as defined above and Y
stands for an aldehyde group, a carboxyl group or
a substituted or unsubstituted allyl group.
Whereas, when A in the formula(I) is a halogen, a
substituted or unsubstituted alkyl group, a substituted
or unsubstituted allyl group, a substituted or unsubsti-
tuted al~oxyl group or a substituted or unsubstituted
aryl group, there is obtained a para-substituted phenol
derivative represented by the formula(III)
o
C ~ D (~II)
A Z
wherein A, B, C, D and E are as defined above,
provided that A does not stand for a hydroxyl
group, a carboxyl group or a sufonic group, and
Z stands for a haloform residue or a substituted
or unsubstituted allyl-grouP.
In the process of the present invention, when said
organic halide is a member selected from a haloform and
a carbon tetrahalide, a hydroxychalcone compound can be
: obtained by,following the step(l) and before the step(2),
(la) adding to said reaction mixture the following
reactant system:
(i) acetophenone or a derivative thereof,
(ii) a carbon tetrahalide and acetophenone in this
- 22 -
~
~3~3~3
order, or
(iii) a haloform and acetophenone or a deriva-tive
thereof in this order,
provided that when said organic halide is a haloform,
the reactant system is a system(i) or (ii), and when
said organic halide is a carbon tetrahalide, the
reaction system is a system(iii), thereby effecting a
reaction to obtain a hydroxychalcone compound as the
para-substituted phenol derivative. The reaction
mixture obtained in the step(l) contains the used fixed
cyclodextrin. In the step(la), the dissolution of the
above-mentioned reactant systems (i) - (iii) into the
reaction system is accelerated by virtue of the presence
of the used fixed cyclodextrin, leading to the accelera-
lS tion of the reaction rate. As a result, a hydroxychalconecompound can be obtained in high yield in a short
period of time. Where the reactant system is a system~i),
there is obtained a 4-hydroxychalcone compound as the
para-substituted phenol derivative. Where the reactant
2Q system is a system(ii), there is obtained a 4-hydroxy-
3-carboxychalcone compound as the para substituted phenol
derivative. Where the reactant system is a system(iii),
there is obtained a 2-hydroxy-5-carboxychalcone compound
as the para~substituted phenol derivative. As the aceto-
phenol derivative, there may be employed, for example,
- 23 -
r.,.
3~L3~3
hydroxyacetophenone,methylacetophenone, nitroacetophenone,
car~oxyacetophenone, sulfoacetophenone, carboxyalkoxy-
acetophenone and sulfoalkoxyacetophenone. In the
preparation of the hydroxychalcone compound, the
acetophenone or its derivative may be employed in an
amount of preferably 1 to 20 mols, more preferably l to
2 mols per mol of the phenol compound used. In this
case, the molar ratio of the fixed cyclodextrin to the
phenol compound is preferably 0.01 to lO, more preferably
0.1 to 5. Where the reactant system is a system(ii),
the carbon tetrahalide is generally employed in an amount
of l to 20 in terms of molar xatio relative to the
phenol compound employed inthe step(l). Where the
reactant system is a system(iii), the haloform is
generally employed in an amount of l to 20 in terms of
molar ratio relative to the phenol compound employed in
the step(l). The reaction temperature in the step(la)
is not critical, but is generally 0 to 120C. In
practicing the process of the present invention, it is
preferred that at the time of addition of the above-
mentioned reactant system to the reaction system, the
conversion be preferably 50 to lO0 % in the reaction of
the reagent, which is different in kind from the reagent
to be now added and which had been added previously,
with the phenol compound or the intermediate derived
therefrom.
- 24 -
~3~93
In the process of the present invention, a
reaction mixture containing an intended para-substituted
phenol derivative is obtained by the above-mentioned
reaction and, thereafter, the catalyst, i.e., the
fixed cyclodextrin can easily be separated and recovered
from the reaction mixture by methods such as centrifuga-
tion and filtration. The recovered solid can be used
again as a catalyst repeatedly. On the other hand, the
remaining reaction mixture from which the catalyst has
been removed is subjected to extraction with ether.
The ether layer is washed with water and then dried to
obtain a para-substituted phenol derivative.
The process of the present invention may be
practiced by passing an alkaline aqueous solution
containing a phenol compound and an organic halide over a
fixed bed of a fixed cyclodextrin, or by contacting the
solution with the fixed bed. For preparing a hydroxy-
chalcone compound, the process of the present invention
may be practiced in such a manner that while passing an
alkaline solution of a phenol over a fixed bed of a fixed
cyclodextrin or contacting the solution with the bed, the
phenol conpo~d is reacted with a haloform and an acetophenone
compound in this order, a haloform, a carbon tetrahalide
and an acetophenone compound in this order, or a carbon
tetrahalide, a haloform and an acetophenone in this
order. In this mode of practice, there is required no
- 25 -
... .
33
operation for separation of the so~id catalyst
by means of centrifugation or filtration.
In practicing the process of the present invention,
when a carbon tetrahalide is used as the organic halide
the reaction may be effected by addin~ a copper catalyst
to the reaction system. As the copper catalyst, there
may be mentioned, for example, copper powders, copper(II)
sulfate, a copper(II) halide and copper(II) oxide. In
general, the copper catalyst is added in an amount of
l to 10 % by weight based on the phenol compound.
~ s apparent from the foregoing, according to the
process of the present invention, not only the intended
para-substituted phenol derivatives can be produced in
high yield and with high selectivity, but also the fixed
cyclodextrin employed as the catalyst can extremely
easily be separated and recovered from the reaction
mixture by means of, for example, centrifugation and
filtration without any loss of the fixed cyclodextrin.
Moreover, the recovered fixed cyclodextrin can be used
repeatedly for the preparation of para-substituted
phenol derivatives without lowering in yield and
selec~ivity. Thus, the process of the present invention
is extremely advantageous from the co~mercial standpoint.
- 26 -
~34~3~
PR~FERRED EMBODIMENTS OF THE INVENTION
.
The present lnvention will be illustrated in more
detail with reference to the following Examples, but
should not be construed as limiting the scope of the
invention. Unless otherwise specified, reactions were
carried out at atmospheric pressure in Examples and
Comparative Examples.
In Examples and Comparative Examples, the yield
of and the selectivity for a produced para-substituted
phenol derivative are respectively those obtained by
the follwoing formulae:
(1) Yield of a para-substituted phenol derivative (%)
mole nu~r of produced para-substituted phenol derivative 100
-
mole number of fed phenol
(2) Sele~ivity for a para-substituted phenol derivative ~%)
mole nu~ber of produced para-substituted phenol derivative
- - - ~ 100
(total of mole numbers of isomers in the~
, ~produced substituted phenol derivativesJ
Example 1
Hydroxyl groups of ~-clclodextrin are crosslinked
with 2-hydroxy-n-propylene group to prepare a solid,
fixed ~-cycLodextrin in the manner as described below.
In 80 ml of an aqueous 50 % sodium hydroxide
- 27 -
3~3~
solution ls dissolved 50 g of ~-cyclodextrin (special
grade reagent, manufactured and sold by Nakarai Chemical
Ltd., Japan). To the resulting solution is added 50 mg
of sodium borohydride (special grade reagent, manufac-
tured and sold by Yoneyama Yakuhin Kogyo Co~, Ltd.,
Japan). 34 ml of epichlorohydrin (special grade reagent,
manufactured and sold by Tokyo Kasei Co., Ltd., Japan)
is dropwise added to the mixture with agitating by
means of a magnetic stirrer. The resulting mixture is
allowed to react at 50 ~C for 40 minutes. The resulting
solid is washed with acetone 3 times and with water
throughly, and then dried in vacuum at 60 C for 12 hours.
Thus, there is obtained 50 g of a fixed ~-cyclodextrin
which is white particles having a particle diameter of
1 to 3 mm. As a result of elementary analysis of the
fixed ~-cyclodextrin, the carbon and hydrogen contents are
found to be 47.0 ~ and 6.6 ~, respectively. Therefore,
the fixed ~-cyclodextrin contains 87 % by weight of
~-cyclodextrin.
To 20 ml of an aqueous 20 ~ of sodium hydroxide
solution are added 1.5 g of the above-obtained fixed
~-cyclodextrin (hereinafter often referred to as
"catalyst") and 1.5 g of phenol (first class grade
reagent, manufactured and sold by Kaso Chemical Co.,
Ltd., Japan), and further are added 3 ml of carbon
tetrachloride (first class grade reagent, Tokyo Kasei
- 28 -
393
Co., Ltd., Japan) and 0.1 g of copper powders (first
class gxade reagent, manufactured and sold by Yoneyama
Yakuhin Kogyo Co., Ltd.). The reaction is allowed
to proceed at 80 C for 15 hours under reflux by
the use of a reflux condenser while agitating by means
of a magnetic stirrer. After completion of the reac-
tion, the catalyst is removed by decantation (recovery
of catalyst: 100 %). The obtained reaction mixture
is acidified with hydrochloric acid, and subjected to
extractions each with 50 ml of ethyl ether 3 times.
The ethyl ether layer is -~ashed with water and then
dried, thereby to obtain 2.1 g of a product. The ob-tained
product is subjected to analysis by liquid chromato-
graphy [using a column (LS410K, MeOH-100, 30 cm) manu-
factured and sold by Toyo Soda Co., Ltd., Japan at 20C, with a mixed solvent of water and ethanol (6:4)].
As a result, it is found that the product is a mixture
of 2.0 g of para-hydroxybenzoic acid and 0.1 g of phenol
and contains no salicylic acid. Namely, the yield of
para-hydroxybenzoic acid is 91 % on molar basis, and
the selectivity is 100 %.
After the above reaction, the above-recovered
catalyst and 1.5 g of phenol are added to 20 ml of an
aqueous 20 % sodium solution. To the resulting mixture
are added 3 ml of carbon tetrachloride and 0.1 g of
copper powder. The reaction is allowed to proceed at
- 29 -
~L23f L39~
80 C for 15 hours under reflux by the use of a reflux
condenser while agitating by means of a magnetic stirrer.
Arter completion of the reaction, the catalyst is removed
by decantation (recovery of catalyst: 100 %). The
resulting solution is acidified with hydrochloric acid,
and subjected to extractions each with 50 ml of ethyl
ether 3 times. The ethyl ether layer is washed with
water, and then dried, thereby to obtain 2.2 g of a
product. The obtained produc-t is subjected to analysis
by liquid chromatography. As a result, it is found
that the product is a mixture of 2.1 g of para-hydroxy-
benzoic acid and 0.1 g of phenol, and contains no
salicylic acid~ Namely, the yield of para-hydroxy-
benzoic acid is 95 % on molar basis and the selectivity
is 100 %
In the same manner as mentioned above, reactions
are carried out repeatedly using the above-recovered
catalyst 5 times. Despite the repeated use of the
catalyst, there is observed no lowering in recovery,
activity and selectivity of the catalyst.
Example 2
Substantially the same reagents and catalyst as in
Example 1 are used,except that o-cresol (special grade
reagent, manufactured and sold by Tokyo Kasei Co., Ltd.,
Japan) is used instead of phenol
To 20 ml of an aqueous 20 % sodium hydroxide
- 30 -
,
~23~3~3
solution are added 1.5 g of the catalyst prepared in
Example l from ~-cyclodixtrin and epichlorohydrin and
1.5 g of o~cresol, and further are added 3 ml of carbon
tetrachloride and 0.1g of copper powder The reaction
is allowed to proceed at 80 C for 15 hours under
reflux by the use of a reflux condenser while agitating
by means of a magnetic stirrer. After comple-tion of
the reaction, the catalyst is removed by
decantation (recovery of catalyst: 100 %). The
resulting solution is acidified with hydrochloric acid,
and subjected to extractions each with 50 ml of ethyl
ether 3 times. The ether layer is washed with water,
and then dried, thereby to obtain 1.9 g of a product.
The obtained product is subjected to analysis by
liquid chromatography [using a column (LS410K, MeOH-100,
30cm) manufactured and sold by Toyo Soda Co., ~td.,
Japan, at 25 C, with a mixed solvent oX water and
ethanol (6:4)]. As a result, it is found that the
product is a mixture of 1.8 g of 3-methyl-4-hydroxy-
benzoic acid and 0.1 g of o-cresol. Namely, the yield
of 3-methyl-4-hydroxybenzoic acid is 85 % on molar
basis, and the selectivity is 100 %.
Example 3
Sbus~antially the same reagents and catalyst as
in Example 1 are used,except that m-cresol tspecial
~:3~3~3
grade reagent, manufactured and sold by Tokyo Kasei Co.,
Ltd., Japan) is used instead of phenol.
To 20 ml of an aqueous 20 % sodium hydroxide
solution are added 1.5 g of the catalyst as prepared
in Example 1 from ~ cyclodextrin and epichlorohydrin
and 1.5 g of m-cresol, and further are added 3 ml of
carbon tetrachloride and 0.1 g of copper powder.
The reaction is allowed to proceed at 80 C for
15 hours under reflux by the use of a reflux condenser
while agitating by means of a magnetic stirrer. After
completion of the reaction, the catalyst is removed
by decantation (recovery of catalyst: 100 %).
The resulting solution is acidified with hydrochloric
acid, and subjected to extractions each with 50 ml of
ethyl ether 3 times. The ether layer is washed with
water, and then dried, thereby to obtain 2.1 g of a
product. The obtained product is subjected to analysis
by liquid chromatography [using a column (LS410K,
MeOH-10, 30 cm) manufactured and sold by Toyo Soda Co.,
Ltd~, Japan, at 25C, with a mixed solvent of water and
ethanol (6:4)~. ~s a result, it is found that the
product is a mixture of 2.0 g of 2-methyl-4-hydroxy-
benzoic acid and 0.1 g of m-cresol. Namely, the yield of
2-methyl-4-hydroxybenzoic acid is 95 ~ on molar basis,
and the selectivity is 100 ~.
~L~3~393
Example 4
__
50 g of ~-cyclodextrin is dissolved in 80 ml of an
aqueous 50 % sodium hydroxide solution~ To the resulting
solution is added 50 mg of sodium borohydride. ~8 ml of
epichlorohydrin is dropwise added to the mixture with
agitating by means of a magnetic stirrer. The resulting
mixture is allowed to react at 50 C for 40 minutes. The
resulting solid is washed with acetone 3 times and with
water thoroughly, and then dried in vacuum at 60 C for
12 hours, thereby to obtain 52 g of a fixed ~-cyclodextrin
which is white particles having a particle diameter of 1
to 3 mm. The elementary analysis of the fixed ~-cyclo-
dextrin shows that the carbon and hydrogen contents are
48.4 % and 7.1 %, respectively. Therefore, the fixed
~-cyclodextrin contains 78 % by weight of ~-cyclodextrin.
The obtained fixed ~-cyclodextrin is used as a catalyst
for the preparation of a para-substituted phenol derivative
as described hereinafter.
To 20 ml of an aqueous 20 % sodium hydroxide
solution are added 1.5 g of the catalyst and 1.5 g of
phenol, and further are added 3 ml of carbon tetra-
chloride and 0.1 g of copper powder. The reaction
is allowed to proceed at 80C for 15 hours under
reflux by the use of a reflux condenser while agitating
by means of a magnetic stirrer. After completion of
the reaction, the catalyst is removed by
- 33 -
.. . .
123~393
decantation (recovery of catalyst: 100 %). The
obtained solution is acidified with a hydrochloric
acid, and subjected to extractions each with 50 ml of
ethyl ether 3 times. The ether layer is washed with
water, and then dried, thereby to obtain 1.9 g of a
product. The obtained product is subjected to analysis
by liquid chromatography [using a column (LS
410K, MeOH-100,30 cm) manufactured and sold by Toyo Soda
Co., Ltd., Japan, at 25 C, with a mixed solvent of water
and ethanol (6:4)] . As a result, it is found that the
product is a mixture of 1.8 g of para-hydroxybenzoic
acid and 0.1 g of phenol. Namely, the yield of para-
hydroxybenzoic acid is 82 % on molar basis, and the
selectivity is 100 %.
Com~arative Exam~le 1
Substantially the same procedures as in Example 1
are repeated for preparing para-hydroxybenzoic acid,
except that 1.7 g of ~-cyclodextrin is used instead of
1.5 g of the fixed ~-cyclodextrin. After completion of
the reaction, the resulting solution is acidified with
1 ml of 36 % hydrochloric acid, and subjected to
filtration to separate ~-cyclodextrin from ~he reaction
solution. The separated ~-cyclodextrin is dried. Thus,
there is obtained 1.4 g of a recovered ~-cyclodextrin
(recovery: ~2 %). On the other-hand, the filtrate is
- 34 -
393
subjected to extrations each with 50 ml of ethyl ether
3 times. The ethyl ether layer is washed with water,
and then dried, thereby to obtain 2.1 g of a product.
The obtained product is subjected to analysis by
liquid chromatography. As a result, it is found
that the product is a mixture of 2.0 g of para-
hydroxybenzoic acid and 0.1 g of phenol, and contains
no salicylic acid. Namely, the yield of para-hydroxy-
benzoic acid -is 92 % on molar basis, and the selectivity
is 100 %.
The synthesis of para-hydroxybenzoic acid
is carried out in substantially the same manner as in
the above,except that 1.4 g of the above-recovered ~-
cyclodextrin is used in combination with 0.3 g of a
fresh ~-cyclodextrin. After completion of the reaction,
the reaction mixture is acldl~ied with a 1 ml of
35 % hydrochloric acid, and subj-ected to filtration to
separate ~-cyclodextrin from the reaction mixture. The
separated ~-cyclodextrin is dried. Thus, there is obtained
1.3 g of-a recover~d ~-cyclodextrin (recovery: 76 %).
On the other hand, the filtrate is subjected to
extractions each with 50 ml of ethyl ether 3 times.
The ethyl ether layer is washed with water, and then
dried, thereby to obtain 2.0 g of a product. The
obtained product is subjected to analysis by
liquid chromatography. As a result, it is found
. . .
~3~L3~
that the product is a mixture of l.9 g of para-hydroxy-
benzoic acid and 0.1 g of phenol and contains no salicylic
acid. Namely, the yield of para-hydroxybenzoic acid is
90 % on molar basis, and the selectivity is lO0 ~.
In the same manner as in the above, the oreparation of para-
hydroxybenzoic acid is repeated 5 -times using the
recovered ~-cyclodextrin while making up the
lost ~-cyclodextrin. As a result,
the recovery of ~-cyclodextrin is 72 to 88 %, and
the yield and selectivity of para-hydroxybenzoic acid
are 85 to 92 % on molar basis and lO0 %, respectively.
Example 5
To 20 ml of an aqueous 20 % sodium hydroxide solution
are added 4.5 g of the catalyst (fixed ~-cyclodextrin)
prepared in Example l and 0.5 g of pher.ol (fi~st class
grade reagent, manufactured by Koso Chemical Co., Ltd.,
Japan). ~he resulting mixture is heated to 60C while
agitating by means of a magnetic stirrer. Then, while
dropwise adding 3 ml of chloroform (special grade reagent,
manufactured and sold by Tokyo Kasei Co., Ltd., Japan) to
the mixture, the reaction is allowed to proceed for 12
hours. During the course of the reaction, chloroform is
added dropwise so that the molar ratio of the fixed cyclo-
dextrin to the chloroform in the reaction system is
maintained at a level of l.0 to 1.6. The control of the
- 36 -
~3~3~;~
molar ratio of the fixed cyclodextrin to chloroform in
the reaction system is effected as follows. Every two
hours during the course of the reaction, part of the
reaction mixture is taken, and subjected to the determina-
tion of chloroform contained therein by means of 701-type
Gas Chromatograph manu~actured by Ohkura Rikagaku Kenkyusho
Co., Ltd., Japan (packing material, Porapak Q manufactured
and sold by Gasukuro Kogyo Inc., Japan; column length,
2 m; column temperature, 30 C; carrier gas, helium), and
the rate of addition of chloroform is adjusted. After
completion of the reaction, the catalyst is removed by
decantation. The recovery of the catalyst is
100 ~. The resulting solution is acidified with
hydrochloric acid, and subjected to extractions each with
50 ml of ethyl ether 3 times. The ether layer is washed
with water, and then dried, thereby to obtain 0.58 g of
a product. The obtained product is subjected to
analy~is by means of Gas Chromatograph (Tenax GC
column, 2 m, 300 C). As a result, it is found that the
product is a mixture of 0.56 g of 4-hydroxybenzaldehyde
and 0.02 g of phenol, and there is detected no 2-
hydroxybenzaldehyde. Namely, the yield of 4-hydroxy-
benzaldehyde is 86 % on molar basis, and the selectivity
is 100 %.
Subsequently, the syn~hesis of 4-hydroxybenzaldehyde
3~3~3
is carried out in substantially the same manner as in the
above, except that the above-recovered catalyst is used.
There is obtained 0.65 g of a product. The analysis of the
product by means of Gas Chromatograph shows that the
product is a mixture of 0.62 g of 4-hydroxybenzaldehyde
and 0.03 g of phenol, and contains no detectable amount
of 2-hydroxybenzaldehyde. Namely, the yield of 4-hydroxy-
benzaldehyde is 96 % on molar basis, and the selectivity
is 100 ~.
Example 6
To 50 ml of an aqueous 20 % sodium hydroxide solu-
tion are added 4.50 g of the catalyst ~fixed ~-cyclo-
dextrin) as prepared in Example 1 and 0.50 g of o-cresol.
The resulting mixture is heated to 60 C while agitating
by means of a magnetic stirrer. Then, while dropwise
adding 3 ml of chloroform (special grade reagent, manu-
factured and sold by Tokyo Kasei Co., Ltd., Japan) to the
mixture in the same manner as in Example 5, the reaction
is allowed to proceed for 12 hours. After completion of
the reaction, the catalyst is removed by decantation.
The recovery of the catalyst is 100 %. The obtained
reaction mixture is acidified with hydrochloric acid,
and subjected to extractions each with 50 ml of ethyl
ether 3 times. The ether layer is washed with water,
and then dried, thereby to obtain 0.65 g of a product.
- 38 -
~23~L3~3
The analysis of the product by means of Gas Chromato-
graph shows that the product is a mixture of 0.61 g of
4-hydroxy-3-methylbenzaldehyde and 0.04 g of o-cresol.
Namely, the yield of 4-hydroxy-3-methylbenzaldehyde is
87 % on molar basis, and the selectivity is 100 %.
Example 7
To 80 ml of an aqueous 10 % sodium hydroxide solu
tion are added 2.0 g of the catalyst (fixed ~-cyclo-
10 dextrin) as prepared in Example 1 and 1.O g (10.8 mmol)
of phenol (first class grade reagent, manufactured and
sold by Koso Chemical Co., Ltd., Japan). Then, while
dropwise adding to the mixture 1.5 ml (18.7 mmol) of
chloroform (special grade reagent, manufactured and sold
by Tokyo Kasei Co., Ltd., Japan) in the same manner as in~xample 5, the reaction is allowed to proceed at 70 C for
10 hours while agitating by means of a magnetic stirrer.
The reaction mixture is cooled thoroughly with ice, and
1.3 g (10.~ mmol) of acetophenone (special grade reagent,
manufactured and sold by Tokyo Kasei Co., Ltd., Japan)
is added little by little to the mixture. The
reaction is allowed to proceed at room tempera-
ture for 10 hours. After completion of the reaction,
the catalyst is removed by decantation. The
recovery of the catalyst is 100 ~. The resulting
solution is acidified with hydrochloric acid, and
- 39 -
,~. .
3~
subjected to extractions each with 50 ml of ether 3 times.
The ether layer is washed with water, and then dried,
thereby to obtain 2.0 g of a product. The obtained product
is subjected to analysis by means of 701-type
Gas Chromatograph manu~actured by Ohkura Rikagaku Kenkyusho
Co., Ltd., Japan (packing material: Uniport ~P manufac-
tured and sold by Gasukuro Kogyo inc., Japan; column
length, 2 m; column temperature, 120 C; carrier gas,
helium). As a result, it is found that the product is
4-hydroxychalcone entirely. Namely, the yield of the
intended product is 84 ~ on molar basis, and the selec-
tivity is 100 %.
Example 8
To 80 ml of an aqueous 20 % sodium hydroxide solution
are added 2.0 g of the catalyst (fixed ~-cyclodextrin)
prepared in Example 1, 1.0 g (10.8 mmol) of phenol and
0.01 g (0.16 mmol) of copper powder (first class grade
reagent, manufactured and sold by Yoneyama Yakuhin Kogyo
Co., Ltd., Japan). Then, whil~ dropwise adding 2 ml
(20.0 mmol) of chloroform (special grade reagent,
manufactured and sold by Tokyo Kasei Co., Ltd., Japan)
to the mixture, the reaction is allowed to proceed at
60 C for 10 hours with agitating by means of a
magnetic stirrer. During the course of the reaction,
the rate of addition of chloroform is controlled accord-
ing to the method described in Example S so that the molar
- 40 -
, . ,
~.~3~3~3
ratio of the fixed 3-cyclode~trin (based on ~-cyclodextrin)
to the chloroform is maintained at a level of 1 to 2.
Subsequently, while dropwise adding 2 ml (24.0 mmol)
of chloroform in the same manner as in Example 5, the
reaction is allowed to proceed at 60 C for 10 hours
with agitating by means of a magnetic stirrer. The
reaction mixture is cooled thoroughly with ice, and 2.5 g
(16.2 mmol) of 4-hydroxyacetophenone (special grade
reagent, manufactured and sold by Tokyo Kasei Co., Ltd.,
Japan~ is added little by little to the mixture.
The reaction is allowed to proceed at room temperature
for 10 hours. Then, the catalyst is removed
by decantation. The recovery of the catalyst
is 100 %. The resulting solution is acidified with
hydrochloric acid, and subjected to extractions each with
50 ml of ethyl ether 3 times. The ether layer is washed
with water, and then dried, thereby to obtain 2.6 g of a
product. The product is subjected to determinations of
infrared spectrum by means of IR-E type-spectrophotometer
manufactured and sold by Japan 5pectroscopic Co., Ltd., Ja~an,
and lH-~MR spectrum by means of PS-100 type high resolution
spectrometer manufactured and sold by Nihon Denshi Co.,
Ltd., Japan. The infrared spectrum and lH-NMR spectrum
of the product are in agreement with those of a standard
sample of 2,4'-dihydroxy-5-carboxychalcone. Namely, the
yield of the intended product is 86 ~ on molar basis and
- 41 -
~;~3~
the selectivity is 100 %.
Example 9
To 80 ml of an aqueous 20 ~ of sodium hydroxide
solution are added 2.0 g of the catalyst (fixed ~-
cyclodextrln) prepared in Example 1, 1.0 g (10.8 mmol)
of phenol and 0.01 g (0.16 mmol) of copper powder.
Then, while dropwise adding to the mixture 2 ml (24.0
mmol) of chloroform in the same manner as in Example 5,
the reaction is allowed to proceed at 60 C for 10
hours with agitating by means of a magnetic stirrer.
Subsequently, while dropwise adding 2 ml (20.0 mmol) of
carbon tetrachloride little by little in the same manner
as in Example 8, the reaction is allowed to proceed at
60 C for 10 hours with agitating by means of a magnetic
stirrer. The reaciton m~re is cooled thoroughly with ice, and
2.2 g (16.2 mmol) of 4-hydroxyacetophenone (special grade
reagent, manufactured and sold by Tokyo Kasei Co., Ltd.,
Japan) is added little by little to the mixture.
The reaction is allowed to proceed at room temperature
for 10 hours. Then, the catalyst is removed
by decantation. The recovery of the catalyst is
100 %. The resulting solution is acidified
with hydrochloric acid, and subjected to extractions each
with 50 ml of ethyl ether 3 times. The ether layer is
washed with water, and ~hen dried, thereby to obtain
- 42 -
,
3~3~
2.8 g of a product. The infrared spectrum and lH-NMR
spectrum of the product are in agreement with those of
a standard sample of 4,4'-dihydroxy-3-car~oxychalcone.
Namely, the yield of the intended product is 92 % on
molar basis and the selectivity is 100 ~.
Example 10
In 80 ml of an aqueous S0 % sodium hydroxide solu
tion is dissolved 50 g of a-cyclodextrin (special grade
reagent, manufactured and sold by Nakarai Chemical Ltd.,
Japan). To the resulting solution is added 50 mg of
sodium borohydride (special grade reagent, manufactured
and sold by Yoneyama Yakuhin Kogyo Co., Ltd., Japan).
34 ml of epichlorohydrin (special grade reagent, manufac-
tured and sold by Tokyo Kasei Co., Ltd., Japan) is drop-
wise added to the resulting mix-ture with agitating by
means of a magnetic stirrer. Then, the reaction is allowed to
react at 50 C for 40 minutes. The resulting solid is washed with
acetone 3 times and with water thoroughly, and then dried
in vacuum at 60 C for 12 hours, thereby to obtain 46 g
of a fixed a-cyclodextrin which is white particles having
a particle diameter of 1 to 3 mm. The elementary analysis
of the fixed a-cyclodextrin shows that the carbon and
hydrogen contents are 44.5 % and 6.3 %, respectively.
Therefore, the flxed a-cyclodextrin contains 82 % by
weight of a-cyclodextrin.
~L23~L3~3
4-Hydroxybenzaldehyde is prepared in substantially
the same manner as in Example 5 except that 4.5 g of
the above-obtained fixed a-cyclodextrin is- used as a
catalyst. The recovery of the catalyst, the yield of
and the selectivity for 4-hydroxybenzaldehyde are 100 %,
58 % on molar basis and 95 %, respectively~
Subsequently, 4-hydroxybenzaldehyde is prepared in
substantially the same manner as in the above, except
that the above-recovered catalyst is used. The recovery
of the catalyst, the yield of and the selectivity for
4-hydroxybenzaldehyde are 100 %, 65 % on molar basis and
95 ~, respectively.
In the same manner as in the above, the syntheses of
4-hydroxybenzaldehyde are carried out repeatedly using
the above-recovered catalyst 5 times. As a result,
the recovery of the catalyst is 100 %, and there is
observed no lowering in activity and selectiviy of
the catalyst.
Example 11
4-HydroxychaLcone is prepared in substantially the
same manner as in Example 7,except that 4.5 g of the
fixed a-cyclodextrin as prepared in Rxample 10 is used
as a catalyst instead of the fixed ~-cyclodextrin. The
recovery of the catalyst, the yield of and the
selectivity for 4-hydroxychalcone are 100 %, 52 % on molar
- 44 -
~3~3~3
basis and 93 %, respectively. In the same manner as in
the above, the syntheses of 4-hydroxychalcone are carried
out repeatedly using the above-recovered catalyst 5
times. As a result, the recovery of the catalyst is
100 %, and there is observed no lowering in activity and
selectivity of the catalyst.
Example 12
2,4'-Dihydroxy-5-carboxychalcone is prepared in
substantially the same manner as in Example 8,except
that 4.5 g of the fixed ~-cyclodextrin prepared in
Example lO is used as a catalyst instead of the ~ixed
~-cyclodextrin. The recovery of the catalyst, the
yield of and the selectivity for 2,4-dihydroxy-5-
carboxychalcone are lO0 %, 53 ~ on molar basis and 93 %,
respectively.
In the same manner as in the above, the syntheses of
2,4'-dihydroxy-5-carboxychalcone are carried out repeatedly
using the above-recovered catalyst 5 times. As a result,
the recovery of the catalyst is 100 %, and there is
observed no lowering in activity and selectivity of the
catalyst.
Example 13
4.4'-Dihydroxy-3-carboxychalcone is prepared in
~L23~3~3~
substantially the same manner as in Example 9,except
that 4.5 g of the fixed ~-cyclodextrin as prepared in
Example 10 is used as a catalyst instead of the fixed
~-cyclodextrin~ The recovery of the catalyst, the
yield of and the selectivity for 4,4'-dihydroxy-3-
carboxychalcone are 100 ~, 51 ~ on molar basis and 92 %,
respectively.
In the same manner as in the above, the syntheses of
2,4'-dihydroxy-3-carboxychalcone are carried out repeat-
edly using the above-recovered catalyst 5 times. As a
result, the recovery of the catalyst is 100 %, and
there is observed no lowering in activity and selectivity
of the catalyst.
Example 14
In 50 ml of an aaueous 1 % sodium hydroxide solution
are dissolved 8.6 g of the catalyst (fixed ~-cyclodextrinj
prepared in Example 10 and 0.2 g of 2,4,6-trimethyl-
phenol (special grade reagent, manufactured and sold by
Tokyo Kasei Co., Ltd., Japan). While dropwise adding
0.9 g of allyl bromide (special grade reagent, manufac-
tured and sold by Tokyo Kasei Co., Ltd., Japan) to the
mixture, the reaction is allowed to proceed at room temper-
ature for 24 hours. During the course of the reaction, the
rate of addition of allyl bromide is controlled according to the method
described in Example 5 so that the molar ratio of the fixed
- ~6 -
.
3~
~-cyclodextrin (based on a-cyclodextrin) to the allyl
bromide is maintained at a level of 1 to 2. Subsequently,
the catalyst is removed by decantation. The recovery
of the catalyst is 100 %. The resulting solution is
acidified with hydrochloric acid, and subjected to
extractions each with 50 ml of ethyl ether 5 times. The
ether layer is dried, thereby to obtain 0.18 g of a
product. The analysis of the product by means of H-NMR
shows that the product contains 53 ~ of 2,4,6-trimethyl-
4-allyl-2,5-cyclohexadienone and that the contents of
2,4,6-trimethyl-6-allyl-2,4-cyclohexadienone and 2,4,6-
trimethylphenyl allyl ether are 26 % and 21 ~, respectively.
Namely, the yield of the intended product is 37 ~, and
the selectivity is 53 %.
In the same manner as in the above, the syntheses of
2,4,6-trimethyl-4-allyl-2,5-cyclohexadienone are carried
out repeatedly using the above-recovered catalyst 5 times.
As a result, the recovery of the catalyst is 1~0 ~, and
there is observed no lowering in activity and selectivity
of the catalyst.
Example 15
A11 the primary hydroxyl groups of a-cyclodextrin
are methoxylated by the method as described in Helv ~Chim.
Acta., 61, 2190 (1978).
In 80 ml o~ an aqueous 50 ~ sodium hydroxide solution
- 47 -
~ 23~3~;~
is dissolved 50 g of the thus modified cyclodextrin, and is
added 50 mg of sodium borohydride (special grade reagent,
manufactured and sold by Yon~yama Yakuhin Kogyo Co., Ltd.,
Japan). To the resulting solution is dropwise added
34 ml of epichlorohydrin (special grade reagent, manufac-
tured and sold by Tokyo Kasei Co., Ltd., Japan) while
agitating by means of a magnetic stirrer. The reaction is
allowed to proceed at 50 C for 40 minutes. The result
ing solid is washed with acetone 3 times and with water
thoroughly, and then dried in vacuum at 60 C for 12
hours. There is obtained 42 g of a fixed modified
cyclodextrin which is white particles having a particle
diameter of 1 to 3 mm. The elementary analysis of the
fixed modified cyclodextrin shows that the carbon and
hydrogen contents are 50.9 ~ and 7.7 ~, respectively.
Therefore, the fixed modified cyclodextrin contains ~0
by weight of the modified cyclodextrin.
2,4,6-trimethyl-4-allyl-2,5-cyclohexadienone is
prepared in substantiall~ the same manner as in
Example 14 except that 8.6 g of the fixed modified cyclo-
dextrin as prepared above is ~sed as a catalyst instead
of the fixed ~-cyclodextrin. As a result, the recovery
of the catalyst, the yield of and the selectivity for
the intended product are 100 %, 48 ~ on molar basis and
78 ~, respectively.
In the same manner as in the above, the catalyst is
- 48 -
~3~3~3
used repeatedly 5 times. As a result, the recovery of
the catalyst is lO0 %, and there is observed no lowering
in activity and selectivity of the catalyst.
Example 16
In 80 ml of an aqueous 50 ~ sodium hydroxide solution
is dissolved 50 g of ~-cyclodextrin and is added 50 mg
of sodium borohydride. 4.8 ml of epichlorohydrin is
dropwise added to the solution with agitating by means
of a magnetic stirrer. The reaction is allowed to proceed
at 50C for 40 minutes. The resulting product is subjected
to purification t~ree times by the reprecipitation method
using an acetone-water system, thereby to obtain a paste-
like catalyst. The measurement of lH-NMR of the catalyst
in heavy water shows that the ratio of ~-cyclodextrin
residue to 2-hydroxypropyl group in the catalyst is
1:1.2 (~-cyclodextrin content: 94 ~ by weight).
To 20 ml of an aqueous 20 ~ sodium hydroxide solu-
tion are added 1.5 g of the catalyst and 1.5 g of phenol,
and further are added 3 ml of car~on tetrac~loride and
0.1 g of copper powder. The reaction is
allowed to react at 80 C for 15 hours under reflex by
the use of a reflux condenser while agitating with a
magnetic stirrer. After completion of the reaction, -the
resulting solution is acidified, and subjected to extrac-
tions each with 50 ml of ether 3 times. The ether layer
- 49 -
39L39~3~
is washed with water r and then dried, thereby to obtain
2.2 g of a produc~. The catalyst is separated from the
water layer by centrifugation (recovery : 100 ~). The
obtained product is subjected to analysis by liquid
chromatography using a column (LS410 K, MeOH-100, ~0 cm)
manufactured and sold by Toyo Soda Co., Ltd~, Japan, at
25 C, with a mixed solvent of water and ethanol (6 : 4).
As a result, it is found that the product is para-hydroxy-
benzoic acid. Namely, the yield of para-hydroxybenzoic
acid is 95 % on molar basis and the selectivity is 100 ~.
Example 17
In 80 ml of an aqueous 20 ~ sodium hydroxide solution
is dissolved 50 g of ~-cyclodextrin ~special grade reagent,
manufactured and sold by Nakarai Chemical Ltd., Japan),
and is added 50 ml of sodium borohydride (special grade
reagent, manufactured and sold by Yoneyama Yakuhin Kogyo
Co., Ltd., Japan). 50 ml of ethylene glycol glicydyl ether
(first class grade reagent, manufactured and sold by Tokyo
Kasei Co., Ltd., Japan) is dropwise added to the solution
with agitating by means of a magnetic stirrer. The
reaction is allowed to proceed at 50 C for 40 minutes.
The produced solid is washed with acetone 3 times and with
water thoroughly, and then dried in vacuum at 60 C for 12
hours. There i5 obtained 44 g of a fixed ~-cyclodextrin
which is white particles having a diameter of 1 to 3 mm~
The elementary analysis of the fixed ~-cyclodextrin shows
.
- 50 -
L3~3~
that the carbon and hydrogen contents are 52.8 % and 8.1 %,
respectively. Therefore, the fixed ~-cyclodextrin contains
60 % by weight of ~-cyclodextrin.
To 20 ml of an aqueous 20 % sodium hydroxide solu-
tion are added 1.5 g o~ the above-obtained fixed ~-
cyclodextrin and 1.5 g of phenol (first class grade
reagent, manufactured and sold by Koso Chemical Co., Ltd.,
Japan), and further are added 3 ml of carbon tetra-
chloride (first class grade reagent, manufactured and
sold by Tokyo Kasei Co., Ltd., Japan) and 0.1 g of copper
powder (first class grade reagent, manufactured and sold
by Yoneyama Yakuhin Kogyo Co., Ltd., Japan). The
reaction is allowed to proceed at 80 C for 15 hours
under reflux by the use of a reflux condenser while agi~
tating by means of a magnetic stirrer. After completion
of the reaction, the catalyst is removed
by decantation (recovery of catalyst : 100 %)~
The resulting solution is acidified with hydrochloric
acid, and subjected to extractions each with 50 ml of
ethyl ether 3 times. The ether layer is washed with
water, and then dried, thereby to obtain 2.0 g of a
product. The obtained product is subjected to analysis
by liquid chromatography [using a column (LS~10 K,
MeO~-100, 30 cm) manufactured and sold by Toyo Soda Co.j
~5 Ltd., at 25 C, with a mixed solvent of water and ethanol
(6 : 4)]. As a result, it is found that the product is
- 51 -
~2~3~;3
a mixture of 1.9 g of para-hydroxybenzoic acid and 0.1 g
of phenol and contains no salicylic acid. Namely, the
yield of para-hydroxybenzoic acid is 86 % on molar basis
and the selectivity is 100 %.
Subsequently, the above-recovered catalyst and
1.5 g of phenol were added to 20 ml of an aqueous
20 % sodium hydroxide solution. To the resulting
mixture are added 3 ml of carbon tetrachloride and
0.1 g of copper powder. The reaction is allowed
to proceed at 80 C for 15 hours under reflux by
the use of a reflux condenser while agitating by means
of a magnetic stirrer. After completion of the reaction,
the catalyst is removed by decantation
( recovery of catalyst : 100 %). The resulting solution
is acidified with hydrochloric acid, and subjected to
extractions each with 50 ml of ethyl ether 3 times. The
ethèr layer is washed with water, and then dried, there~y
to obtain 2.2 g of a product. The product is subjected to
analysis by liquid chromatography. As a result, it is
found that the product is a mixture of 2.1 g of para-
hydroxybenzoic acid and 0.1 g of phenol and contains no
salicylic acid. Namely, the yield of and the selectivity
for para-hydroxybenzoic acid are 95 ~ on molar basis and
100 ~, respectively.
In the same manner as in the,above, the catalyst is used
repeatedly 5 times. As a result, there is observed no lower-
ing in recovery, activity and selectivity of the catalyst.
- 52 -
i
~ 23gL~3
PROBABILITY OF UTILIZATION IN INDUSTRY
According to the process of the present invention,
not only a variety of useful para-substituted phenol
derivatives can be prepared from phenol compounds in
high yield and with high selectivity, but also the fixed
cyclodextrin employed as the catalyst can extremely
easily be recovered from the reaction mixture by means
of, e.g., centrifugation and filtration without any loss
of the fixed cyclodextrin. Moreover, the recovered fixed
cyclodextrin can be used repeatedly as a catalyst in the
process of the present invention without lowering in
yield of and selectivity for para-substituted phenol
derivatives, thus enabling the commercially advantageous
production process of the desired products to be realized.
. ,
