Note: Descriptions are shown in the official language in which they were submitted.
~33~6
This invention relates to a process for preparing an
aromatic acetic acid represented by the formula
ArC~2COOH (I)
wherein Ar is a substituted or unsubstituted aromatic group.
~ore particularly, this invention relates to a process for
preparing an aromatic acetic acid represented by the formula
~I) above which comprises reacting an aromatic aldehyde repre-
sented by the formula
ArCHO - ------------ - (II)
wherein Ar is a substituted or unsubstituted aromatic group,
with an alkanethiol represented by the formula
RSH - (III)
wherein R is an alkyl group, and a trihalomethane represented
by the formula
~CX3 (IV)
wherein X is a halogen atom, in the presence of a base in a
mi~ed medium of water and a non-protonic polar solvent.
Certain types of substituted aromatic acetic acids have
been known to exhibit antipyretic, anti-inflammatory, analgesic
and antispasmodic activities and have been practically used
as pharmaceuticals. Also, some of the aromatic acetic acids
are utilized as chemical modifier for antibiotics and, in
addition, are used as raw materials for the production of new
types of pyrethroid insecticidal agents. Accordingly, develop-
ment on a novel process for easily synthesizing these useful
substituted aromatic acetic acids will greatlylcontribute to
the chemical industry.
:,
~33~
Hitherto, the above type of compounds have been prepared
by the following processes:
1) Process comprising heating a halobenzene and an a-halo-
acetic a_id ester in the presence of copper powder [refer to
Th. Zinc~e, Ber., 2, 738 (1869)].
2) Process comprising con~erting a halogsnated benzyl as raw
material into a Grignard rea~ent followed by carboxylation
[refer to J. Houben, ~er., 35, 2523 (1902)1.
3) Process by Arndt-Eistert-Wolff reaction of diazoaceto-
10 ~ phenone [refer to L. Wolff, Ann., 394, 43 (1912)].
4) Process comprising acetylatins an aromatic compound
followed by heating together with ammonium polysulfide and
then hydrolysis tWoE~ Bachmann et al., J. Amer. Chem. Soc.,
65, 1329 (19~3)].
5) Process comprising treating a halogenated benzyl with
sodium cyanide, potassium cyanide or the like to form an
aromatic substituted acetonitrile which is then hydrolyzed
with an alkali or an acid into the aromatic acetic acids [refer
to A.W. Hofmann, Ber., 7, 519 (1874); R~ Adams and A.F. Thal,
Orq. Synth., Coll. Vol. Ij 436 (1947)].
6) Process comprising reacting an aromatic aldehyde with
formaldehyde mercaptal S-oxide followed by treating with a
mineral acid to convert into the aromatic acetic acid deriva-
tives lrefer to ~. Ogura et al., Tetra. Letters, 1383 (1972)].
7) Process comprising synthesis of aromatic acids by treat-
ing a 2,2,2-trihalo-1-arylethanol with water, an alcohol, a
mercapta~ or an amine in the presence of a base to prepare the
corresponding -oxy, ~-thio or ~-amino-substituted aromatic
acetic acid and removing the ~-substituent by reduction pro-
cedure trefer to Japanese Patent Application Publication
(Unexamined) Nos. 112836/1978 and 112868/1978].
:
~33~
However, in the processes 1) and q), the reaction condi-
tions are very difficult to determine and also the reaction
yield is generally low. In carrying out the process 2),
anhydrous reaction condition must be established. The process
3) requires unstablc diazo compounds as starting materials.
In the proce~s 5), the starting material halogenated benzyls
are noteasily available and, in addition, the process must
proceed via a highly toxic cyanide. The process 6) requires
a number of reaction steps. The process 7) also requires a
number of reaction steps since the process requires the synthesis
of an c-substituted-phenyl acetic acid and then reduction.
Such disadvanta~es associated with these conventional processes
prevent the practical use of these processes in industry and
in general when substituents to be retained on the aromatic
ring have previously been introduced into the aromatic ring,
these conventional processes cannot easily be used practically.
- As a result of extensive researches in order to eliminate
the disadvantages of the conventional processes, the present
invenotrs found a process for the synthesis of the desired
aromatic acetic acids represented by the formula tI~ above
~hrough a one-step reaction from aromatic aldehydes represented
by the formula (II) which are easily available in industry and
completed the present invention.
, Examples of aromatic aldehydes represented ~y the formula
(II) above used as starting materials are (alkyl-substituted
phenyl)aldehydes such as benzaldehyde, tolualdehyde, ethylbenz-
aldehyde and the like, (aryl-substituted phenyl)aldehydes such
as phenylbenzaldehyde, (mono- or dialkoxy-substituted phenyl)-
ildehydes and (aryloxy-substituted phenyl)aldehydes such as
anisaldehyde, etho~ybenzaldehyde, allyloxybenzaldehyde, benzyl-
oxybenzaldehyde, piperonal, phenyloxybenzaldehyde, benzyloxy-
benzaldehyde and the like, (halo-substituted phenyl)aldehydes
:
--3--
, ,:' ~ ' , ' ' , .. :
: : :~:,
.:
~339~
such as chloroben~aldehyde, bromobenzaldehyde and the like,
lalkyl, alkoxy or aryloxyhalo-di-substituted phenyl)aldehydes
such as aminobenzaldehyde, meth~l chLorobenzaldehyde, methoxy-
chlorobenzaldehyde, allyloxychlorobenzaldehyde, phenoxychloro-
benzaldeh~de and the like, unsubstituted or substituted aromatic
aldehydcs such as thiophenealdehyde, furylaldehyde, naphthyl-
aldehyde and the like. These aldehydes are easily available
in industry.
Examples of alkanethiols represented by the formula(III)
above used as starting material in the present invention are
methanethiol, ethanethiol, propanethiol, butanethiol and the
like. For ease in handling and availability, lower alkane-
thiols are preferably used.
~xamples of trihalomethanes of the formula (IV) above
~hich can be used are tribromomethane, trichloromethane, di-
bromochloromethane, dichlorobromomethane and the like.
The present invention is conducted in the presence of
a base as an essential requirement. The bases include alkali
metal hydroxides such as potassium hydroxide, sodium hydroxide,
lithium hydroxide and the like, alXali metal carb~nates such
as sodium carbonate, potassium carbonate and the like. Pra-
ferably, alkali metal hydroxides are used as base since the
reaction time can be shortened and the yield of the product
can be impro~ed.
The present invention is also conducted in a mixed solvent
of water and a non-protonic polar solvent as an essential
requirement. Examples of non-protonic polar solvents which can
be ~sed are sulfoxides such as dimethyl sulfoxide, sulfones
such as sulforane, amides such as dimethylformamide, dimethyl-
acetamide, hexamethylphosphoramide and the like, nitriles such
as acetonitrile and the li~e, ethers such as tetrahydrofuran,
dimethoxyethane, diglyme and the like, or a mixture thereof.
~he use of dimethylformamide is preferred in order to obtain
the desired compound in high selectivity and high yield.
-:
~33~
From the standpoints of yield and reaction selectivity, water
and a non-protonic polar solvent are preferably used at a ratio
of about l:l by volume.
The reaction i5 carried out by dissolving the com-ounds
of the formulae (II), ~III) and (IV) in the above medium and
then adding thereto a base dissolved in the above medium, but
the order of addition can be changed depending upon the type
of the starting aldehyde (II). ~he alkanethiol (III) is pre-
ferably used in an amount of 2 to 7 times in equivalent with
respect to the ar~matic aldehyde (II). The trihalomethane is
used in an equal amount to a slightly excess amount. The base
is preferably used in a stoichiometrically required amount,
i.e., 5 to 8 equivalents, with respect to the stdrting materi-
al (II). The reaction does not require speciric heating or
cooling and proceeds easily at room temperature, but, if neces-
sary, the reaction can be carried out wlth slightly cooling
or heating to promote the reaction and to improve the yield.
According to the present invention, the aromatic acetic
acid represented by the formula ~I) above corresponding to the
aromatic aldehyde represented by the formula (II) above can
be prepared. ~xamples of aromatic acetic acids obtained by
the present invention are (alkyl-substituted phenyl)acetic acids
such as (methyl-substituted phenyl~acetic acid, (ethyl-sub-
stituted phenyl)acetic acid and the like, (aryl-substituted
~ phenyl)acetic acids such as (phenyl-substituted phenyl)acetic
acid and the like, (mono- or dialkoxy-subs~ituted phenyl)-
acetic acids and (aryloxy-substituted phenyl)acetic acids such
.
~L3L33~
as (methoxy-substituted phenyl)acetic acid, ~ethoxy-substituted
phenyl)acetic acid, (allyloxy-substituted phenyl)ace~ic acid,
~benzyloxy-substituted phenyl)acetic acid, (methylenedioxy-
substituted phenyl)acetic acid, (phenoxy-substituted phenyl)-
acetic acid and the like, (halo-substituted phenyl)acetic acids
such as (chloro-substitute~ phenyl)acetic acid, (bromo-substi-
tuted phenyl)acetic acid and the like, (amino-substituted
phenyl)acetic acid, (alkyl- or alkoxy, aryloxy, halo-substituted
phenvl)acetic acids such as methoxychloro-di-substituted phenyl)-
acetic acid, (ethylchloro-di-substituted phenyl)acetic acid,
(methoxychloro-di-substituted phenyl)acetic acid, (allyloxy-
chloro-di-substituted phenyl)acetic acid, (phenoxychloro-di-
substituted phenyl?acetic acid and the like, unsub~tituted or
substituted aromatic acetic acids such as pheny~acetic acid,
thienylacetic acid, furylacetic acid, naphthylacetic acid and
the like.
In considering the present invention form the reaction
mechanism, the main reaction route for obtaining the aromatic
acetic acids (I) from the aromatic aldehydes (II) can be
represented by the following reaction scheme.
ArC80 + CHX3 Base -~ Ar-CH-Cx3
(II) (IV) 0 ~
(~ase)
' . ' .,,' : . :~'
' '' , ' .
-
ArCHCOX ~ R5~ ~ O
T~ase
9 ~ ~ase _ RSH (III
¦~ase
RS9
ArC~COSR - - ~ ArCH2COSR
SR
~ 8ase
ArCH2COOH ~ RS~
(I) ~Regeneration)
That is, the reaotion proceeds via the formation of a
2,2,2-trihalo-1-arylethanol by addition reaction of an aromatic
aldehyde and a trihalomethane in the presence of a base, the
for~ation Oc a dihalo epoxide b~ a base, the ring-openin~ reac-
tion of the epoxide by a mercaptide anion, the cleavage of an
~-thio substituent from an a-thio-substituted aromatic acetic
acid derivative by the mercaptide anion, hydrolysis, etc. The
use of a highly nucleophilic alkanethiol (Il) and the above-
descrl~ed polar mixed medium which enables a smooth nucleo-
philic substitution reaction makes it easy that the mercaptide
anion acts nucleophilically on the ~-thio-substituted aromatic
acetic acid derivative produced as intermediate, whereby the
~L33~6
aromatic acetic acid frcm which the ~-thio substituent has
been removed can be obtained directly.
The present invention is further illustrated in greater
detail by the following Examples and Comparative Examples.
Exam~e 1
To a 50~ dimethyl sulfoxide aqueous solution (25 ml) were
added methyl mercaptan (0.95 g, 20 mmoles), an aqueous solu-
tion (5 ml) of potassium hydroxide (0.3 g, 5.3 ~moles), a
dimethyl sulfoxide solution (5 ml) of o-benzyloxybenzaldehyde
tl.06 g, 5 mmoles) and then bromoform (1.52 g, 6 mmoles) while
cooling with ice-water and stirri~g, and the mixture was stirred
for 30 minutes. Potassium hydroxide (2.0 g, 3; mmoles) dis-
solved in a S0~ dimethyl sulfoxide aqueous solution (15 ml) was
added dropwise to the reaction mixture. After completion of
the addition, the mixture was stirred at room temperature
overnight and at 70C for 2 hours. ~fter cooling to room tem-
perature, water and diethyl ether were added thereto and tne
ether-soluble .material was removed. The aqueous layer was ren-
dered acidic with dilute hydrochloric acid and extracted with
ethyl acetate. The extract was washed with water, dried over
anhydrous magnesium sulfate and filtered. The filtrate was
concentrated and purified by silic~ gel column chromatography
, to a~Eord 0.78 g (64~) of p-benzyloxyphenylacetic acid.
N~R (CDC13, ~TMS): 3.68 (s, 2H),'5.03 ts, 2H), 6.73-7.53
(m, 9H), 10.~ tbs, lH).
~33~6
Example 2
To a 50% dimethyl sul~oxide aqueous solution tS0 ml)
were added ethyl mercaptan (3.5 ml, 47 mmoles), an aqueous
solution (10 ml) of potassium hydroxide (0.6 g, 10 ~moles), a
solution of 2-thienyl aldehyde (1.12 g, 10 mmoles) in dimethyl
sulfoxide (10 ml) and then bromoform (3.04 g, 12.2 mmoles) in
an argon atmosphere .~hile cooling with ice--~ater and stirring,
and the mixture was stirred for 1 hour. Potassium hydroxide
(3.04 g, 46 mmoles) dissolved in a 50~ dimethyl sulfoxide
aqueous solution (30 ml) was added dropwise to the reaction mix-
ture. After cornpletion of the addition, the mixture was stirred
for 2 hours and then at room temperature for 3 hours. Water
and diethyl ether were¦added to the reaction mixture and the
ether-soluble material was removed. The aqueous layer was
rendered acidic with dilute hydrochloric acid and extracted
with chloroform. The extract was washed with water, dried over
anhydrous magnesium sulfate and filtered. The filtrate was
concentrated and purified by silica gel chromatography to afford
0.82 g (58~) of thienylacetic acid.
NMR (CDC13, ~TMS): 3.8 (s, 2H), 6.80-7.23 (m, 3H), 11.2
~bs, lH).
Example 3
To a 50% dimethyl sulfoxide aqueous solution (50 ml)
were added methyl mercaptan (2.5 g, 52 mmoles), an aqueous solu-
tion llO ml) of potassium hydroxide (0.6 g, 10 mmoles), a solu-
tion of p-methoxybenzaldehyde (1.36 g, 10 mmoles) in dimethyl
sulfoxide (10 ml) and then bromoform ~3.04 g, 12.2 mmoles)
_g _
:
: - : . . . .
~i339~;
while cooling with ice water and stirring, and the mixture was
stirred for one hour. Potassium hydroxide (3.04 g, 46 ~oles)
dissolved in a S0~ aqueous solution of dimethyl sulfoxide
(30 ml) was added dropwise to the reaction mixture. After
completion of the addition, the mixture was stirred overnight
at room temperature and then 2 hours at 70C. Aft2r allowing
the mixture to cool to room temperature, water and diethyl
ether were added to the reaction mixture and the ether-soluble
material was removed. The aqueous layer was rendered acidic
~-ith dilute hydrochloric acid and extracted with ethyl acetate.
The extract was washed with water, dried o~er anhydrous magne-
sium sulfate and filtered. The filtrate was concentrated and
purified by silica gel chromatography to afford 1.64 g of
crystals. Upon measurement of N~IR spectrum of the resulting
crystals and gas chromatography determination of the correspond-
ing methyl ester obtained by treating the crystals with dia70-
methane (2% EGA, 1 m, temperature increase at a rate of 1C/min
from lS~ C), the isolated crystals were found to be a mixture
of p-methoxyphenylacetic acid and ~-methylthio-p-~ethoxyphenyl-
acetic acid at a ratio of 92:8. That is, the yield o~ p-
methoxyphenylacetic acid was 87% based on p-methoxybenzaldehyde.
Examples 4 - 28
In the same manner as Example 3, aromatic acetic acids
w~re synthesized using the aromatic aldehydes as starting
materials shown in the following reaction scheme. The re-
sults obtained are shown in Table I.
-10-
~ ~339:~
RSH (III), HC8r3, Potassium Hydroxide
Ar-CHO - - -~ Ar-CH2COOH
50~ Dimethyl Sulfoxide Aqueous Solution
~II) (I)
Table I
Example Ar R ~IIX) Yi~ld (~)
4 Ph Me 52
" Et 77
6 n n-Pr 4 9
7 " i-Pr 31
8 ~ t-Bu 53
9 CH3 ~ Me 57
" Et 72
11 " n-Pr 76
12 " i-Pr 43
13 " t-Bu 70
14 C1 ~ Me 55
" Et 82
16 " n-Pr 71
17 " i-Pr 73
18 " t-Bu 35
19 MeO ~ Et 79
" n-Pr 87
21 " i-Pr 84
22 n t-Bu 92 .
23 Ph O ~ Me 30
2 4 Me2N ~ Me 3
--11--
~ ~335~gL6
Example _ Ar _ R (III) Yield (%)
~ ~ Me 58
26 ~ " 64
27 " Et 88
28 ~ ~e 59
Example 29
To a mixed solvent of acetoni~rile (25 ml) and water (10 ml)
were added l-methyl-2-formyl-5-p-methylbenzoylpyrrole (1.135 g,
5 mmoles), bromoform ~1.;4 g, 6.1 mmoles) and ethyl mercaptane
tl.61 g, 26 mmols, 1.94 ml). A solution of potassium hydroxida
(1.57 g, 28 mmols) dissolved in water (7.5 ml) and acetonitrile
(25 ml) was added dropwise thereto at r.t. under stirring.
After the addition was over, the reaction mixture was stirred
overnight at r.t. and heated under stirring at 80C in a hot-
water bath for 2 hrs. After allowing the mixture to cool to
r.t., water (50 ml) was added thereto, diiuted and washed with
ether. The aqueous layer was taken out and acidified with HCl.
The reac~lon mixture became white turbid to form a solid.
This solid was extracted with ether, dried and concentrated to
afford 0.9 g of 5-p-methylbenzoyl-1-methylpyrrole-2-acetic acid.
Yield 70~.
m.p.: 155 - 156C
NMR tCDC13): ~2.37 ~3H, s), 3.69 (2H, s), 3.89 (3EI, s),
6.06 ~lH, d, J=4Elz), 6.62 ~lH, d, J=4Hz),
7.18 ~2H, d, J=8Hz), 7.6~ (2H, d, J=8Hz).
IR ~K~r): 3425, 2940, 2900, 1700, 1610 cm 1.
-12-
- ~ : : :: ,~ :
.: ;- : :. , . : :; , :
- : : . .:: .~., : :
~3L3~9~
om~arative Exarnple 1
(Embodiment where i-propanol was used as a reaction solvent
and the a-phenylthio group was cleaved.)
To a solution of thiophenol (1.65 g, 1; mmoles)~ bromo-
form (3.04 g, 12 m~oles), and p-methoxybenzaldehyde (1.4 g,
10 m~oles) dissolved in i-propanol (50 ml) was added a solution
of potassium hydroxide (3.4 g, 53 mmoles) dissolved in i-
propanol (50 ml) while cooling with ice-water and stirring.
A~ter c_mpletion of the addition, the mixture was stirred
overnight at room temperature and then refluxed for 3 hours.
After allowing the mixture to cool to room te~perature, water
and diethyl ehter were added thereto to remove ether-soluble
material. The aqueous la~er was rendered acidic with dilute
hydrochloric acid and extracted with chloroform. The extract
was washed with water, dried sver anhydrous magnesium sulfate
and filtered. The filtrate was concentrated and purified by
silica gel column chromatography to afford a-phenylthio-p-
methoxyphenylacetic acid (2.69 g, 96~).
NMR ~CDC13, ~T~S): 3.74 (s, 3H), 4.79 ~s, lA), ~.02 (m,
2n aromatic's H), 9.84 (bs, lH).
Comearative E~amole 2
~Fmbod~ent where ethanol was used as a reaction solvent and
the a-phenylthio group was not cleaved.)
25 ~ The experiment was conducted using the same starting materi-
~ls ant the same reaction procedures as used in Comparative
Example 1 but using ethanol as a reaction solvent also resultad
in the production of a-phenylthio-p-metho~yphenylac_tic acid
~2~35 g, 84~).
3~
