Note: Descriptions are shown in the official language in which they were submitted.
11;26Z82
This invention rela-tes to a novel process for
preparing xanthone derivatives of interest in the treatment
of allergic conditions.
According to the present invention, there is provided
a process for the preparation of compounds of general formula I,
O O
Rl-S ~ COOR (I)
R
wherein R represents a hydrogen atom or an alkyl radical
containing from 1 to 9 carbon atoms and Rl represents an alkyl
radical containing from 1 to 5 carbon atoms, which comprises
cyclising a compound of formula II,
0 R800C
Rl-SI~ ~ ~ CO~R2 (II)
wherein R and Rl are as defined above and R2 and R3, which
may be the same or different, each represents an esterifying
group, followed, if required, by hydrolysis to the free acid.
The compounds of general formula I, as well as
processes for their preparation, are described in our British
Patent Specification N 1,518,083. As indicated therein they
possess interesting anti-allergic activity and are, in particular,
of importance in the treatment of allergic asthma and asthmati-
form bronchitis of allergic origin. According to the present
invention, these compounds may be prepared with good yields and
in fewer stages than required in the hitherto known processes.
In general, R is preferably n-hexyl and Rl is preferably methyl.
In the compound of formula II, R2 and R3 may, for
'. - 1 - ~
11;2~282
example, each represent an alkyl radical containing from 1
to 3 carbons, an aryl, e.g. nitrophenyl radical, an aralkyl, e.g.
nitrobenzyl radical or a dialkylaminoalkyl , e.g. dimethyl-
aminoethyl radical. According to a preferred embodiment the
- esterifying groups R2 and R3 are such as to enable the compound
of formula II to be obtained in a crystallized form so as to
facilitate the preparation of pure compound of formula II.
Cyclisation of the compound of formula II is conven-
iently effected by means of a strong acid such as, for example,
~ 0 polyphosphoric or concentrated sulphuric acid, in which case
hydrolysis to the free acid generally takes place simultaneous-
ly or, for example on addition of water. Where, however, the
corresponding ester is obtained, hydrolysis to the free acid
may take place in a separate stage according to conventional
methods. Preferred temperatures for the cyclisation are about
o oc.
The compound of formula II may, for example, be
obtained, if desired in situ, by reaction of a compound of
formula III,
R300C
., 11 \
U1-5 ~ ~ /C~2 (III)
R
where R, Rl, R2 and R3 are as defined above, with an alkali
metal azide or with an 0-hydrocarbon-sulphonyl-hydroxylamine.
Preferred 0-hydrocarbon-sulphonyl-hydroxylamines
are aromatic sulphonyloxy compounds e.g. 0-mesitylene-sulphonyl~
hydroxylamine. The reaction is conveniently effected at ambient
temperatures and preferably in the presence of a chlorinated
organic solvent e.g. c3ichloromethane.
.
` ; il26;~:82
.. . .
When an alkali metal azide is employed this is
~' preferably sodium azide. Preferably the reaction is effected
-i in an anhydrous acid medium e.g. in the presence of poly-
phosphoric acid and at temperatures of from ambient temperature
to 50C. As will be appreciated, when the reaction is effected
: in the presence of an acid, the product will be obtained in
acid solution in which case, providing the acid is a strong
acid, cyclisation and hydrolysis to give the desired compound
of formula I may be effected merely by heating of the reaction
mixture followed by addition of water.
The compound of formula III may, for example, be
prepared by reaction of a compound of formula IV,
~ o
11
Rl \ ~ ~ (IV)
~ OH
: : ;
wherein R and Rl are as defined above, with a compound of
formula V,
R500C ,, COOR4
," ~ (V)
Hal
wherein R4 and R5, which may be the same or different, each
... .
represents an esterifying group, for example such as exemplified
hereinabove in relation to the groups R2 and R3 and Elal re-
presents a chlorine, bromine or iodine atom,in the presence
..
o, of a weak base and of metallic copper or a copper oxide,
preferably in the form of a powder. The weak base may be,
for example an alkali metal carbonate e.g. sodium or potassium
carbonate.
- 3 -
1126282
In the related process described in our above-
mentioned Patent Specification N 1,518,083, the phenol
; component carries a grouping RlS- instead of RlSO - and
oxidation is effected after the coupling reaction. However
in this previously described reaction, temperatures above
150C reduce yields due to side reactions although the coupling
reaction proceeds better at higher temperatures. An advantage
' of the present method, therefore, is that the coupling reaction
can be effected at higher temperatures, for example, in the
range 160 - 180C, e.g. 170C. The substituent Hal is prefer-
ably bromine. The product of formula III is often difficult
to purify, being an oil, and it may be advangageous to effect
! saponification, for example with an alkali metal hydroxide,
e.g. sodium or potassium hydroxide, to give a compound of
formula VI,
O HOOC
¦l \ COOH
Rl ~ - ~ ~ (VI)
R
wherein R and Rl are as defined above, which compound of formula
VI may then, after purification by crystallisation, be ester-
ified with an appropriate alcohol to give the desired compound
of formula III. Such a process may also be of use when it is
desired to change the esterifying groups, for example to
esterifying groups enabling easier purification of the product
due to the formation of a crystalline product or to esterifying
groups which are sensitive to reactions used in preparing the
compound of formula V and thus could not be introduced earlier.
i 3() When re-esterification is effected, the diacid or a
reactive derivative thereof may be reacted with an appropriate
alcohol. When the diacid itself is used the reaction is
- 4 -
.
l:lZ6Z8;~
,
preferably effected in the presence of an acid or a carbodiimide
reagent such as e.g. carbonyldiimidazole or dicyclohexyl-
carbodiimide. Where relatively complex esters are required
it may be convenient to convert the diacid into a reactive
derivative thereof such as a diacid halide, e.g. by reaction
with a reagent such as oxalyl chloride or thionyl chloride or
bromide, followed by reaction with the alcohol.
The phenol of formula IV may be prepared from a
phenol of formula VII,
Rl-S
(VII)
OH
R
where Rl and R have the above meanings, by oxidation, e.g.
using a periodate such as sodium metaperiodate or a peroxide
oxidising agent. The reaction may, for example be effected
in the presence of a lower alkanol as solvent and advantageously
under reflux.
- 20 The following non-limiting Examples serve to illustrate
the invention:
EX~MPLE 1
(S-Methvlsulphonimidoyl)-5-(n-hexyl)-xanthone-2-carboxylic acid.
Step A : 2-(n-hexyl)4-(methylsulphinyl)-phenol
A solution of 2-(n-hexyl)-4-(methylthio)-phenol
(2.24g) in ethanol (50 ml) was heated under reflux and a
solution of sodium metaperiodate (3.2 g) in water (20 ml) was
added dropwise thereto. The mixture obtained ~as stirred
under reflux for a further 30 rnins then cooled, filtered and
diluted with water. The resultant mixture was ext~acted with
ether. Evaporation of the ether extract gave 2-(n-he yl)-4-
(methylsulphinyl)-phenol as a red oil (2.72 g, 100% ~). I`he
` -```- ` l~'~Z~32
` product was obtained as a low melting white solid (M.Pt. 45.5-
47) after chromatography and low temperature crystallisation.
I.R. Spectrum ~~S0 = 1020 cm 1 (sulphoxide S0)
~OH = 3~50 cm 1 (phenol OH)
N.M.R. Spectrum (CDC13)
2.58~ td,J = 2.5 Hz) - H-3
` 2.64~ (q,J = 2.5 and 8.0 Hz) - H-5
3.04~ (d,J = 8.0 Hz) - II-6
7 27~ (s) - -SO-CH3
7.36~ (t,J = 7.5 Hz) - Ar-CH2-CH2-
8.1 - 9. 3~ ( broad m) - -CH2-(CH2) 4-CH3
9.13~ (t,J = 5.5 HZ) - CH3-CH2-
Step B : 4-~4'-methylsulphinyl-2'-(n-hexyl)-phenox
isophthalic acid
A solution of 2-(n-hexyl)-4- (methylsulphinyl)-phenol
(2.4 g) and dimethyl 4-bromoisophthalate (2.73 g) in dry
nitrobenzene (20 ml) was treated with copper powder (0.2 g)
and potassium carbonate (2.8 g). The mixture obtained was
stirred vigorously for six hours at 170-180 under a stream
of dry nitrogen gas. The resultant black reaction mixture
~as cooled and treated with a solution of sodium hydroxide
(1.6 g) in ethanol (22 ml) and water (8 ml). The mixture thus
obtained was heated under reflux for a further one hour to
hydrolyse the diester. The reaction mixture was then cooled,
diluted with water and the nitrobenzene was extracted into
dichloromethane. The remaining aqueous extract was washed
again with dichloromethane, acidified with conc. hydrochloric
acid and re-extracted with chloroform. The organic extract
was washed with water, dried over magnesium sulphate and
evaporated leaving 4- /4'-methylsulphinyl-2'(n-hexyl)-phenoxy~-
isophthalic acid as a dark red viscous gum/glass. The crude
product was dried in vacuo and then ground up in a pestle and
-- 6 --
llZ6Z8%
mortar to a fine brown powder (2.84 g, 70%) N.M.R. Spectrum
td6 - DMSO)
1.58~ (d,J = 2.5 Hz) - H-2
; 1.93~ (q,J = 2.5 and 8.5 Hz) - H-6
2.34~ (d,J = 2.5 Hz) - H-3'
2.44~ (q,J = 2.5 and 8.5 Hz) - H-5'
2.98~ (d,J = 8.5 Hz)
- H-5 and H-6'
3.05~ (d,J = 8.5 Hz)
7 . 26l (s) - SOCH3
0 7~37L (t,J = 7.0 Hz) - Ar-CH2-CH2-
8.1 - 9,4r (broad m) - -CH2-CH2-
9.20- (t,J = 5.5 Hz) - CH3-CH2-
Step C : diethyl 4-/4'-methylsulphinyl-2'-(n-hexyl)-phenoxy7-
isophthalate
A solution of 4-/4'-methylsulphinyl-2'-(n-hexyl)-
phenox ~-isophthalic acid (0.1 g) in ethanol (10 ml) was treated
with ten drops of conc. sulphuric acid and the solution obtained
was heated under reflux for four hours, then cooled and poured
, into water. The resultant solution was basified with sodium
carbonate and then extracted with ethyl acetate.
The organic extract was washed with water, dried
over magnesium sulphate and the solvent was evaporated leaving
diethyl 4- ~ '-methylsulphinyl-2'-(n-hexyl)-phenoxyJ-isophthalate
as yellow viscous oil (O.l g, 88%). (The product was obtained
pure by column chromatography on silica gel, eluting with
; chloroform),.
I.R. Spectrum ~CO = 1725 cm (ester CO)
~CO = 1050 cm (sulphoxide SO)
N.M.R. Spectrum CDC13)
1.39~ (d,J = 2.5 llz) - ~1-2
1.88- (q,J = 2.5 and 8.5 flz) - H-6
2.38 L (d,J = 2.5 ~Iz) - ~-3'
- 7 ~
. ~ ,
6282
2.57, (q,J = 2.5 and 8.5 iIz) - H-5'
- 3.10~ (d,J = 8.5 Hz)
- H-5 and H-6'
3.14Z (d,J = 8.5 Hz)
5.62r (q,J = 7.0 Hz) _ _
- 2X/-o-cH2-cH3J
5.69~ (q,J = 7.0 Hz)
7.29L (s) - SOCH3
7.30~ (t,J = 7.5 Hz) - Ar-CH2-CH2-
8.1 - 9~4 r ( broad m) - -CH2-(CEI2)4-CH3
8.62r (t,J = 7.0 EIz)
- 2x /-O-CH -CII J
8.73~ (t,J = 7.0 Hz) 2 -3
9 15r (t,J = 5.5 Hz) - CH3-CH2-
Step D : diethyl 4-/4'-(S-methylsulphonimidoyl)-2'-(n-hexyl)-
phenoxy 7-isophthalate
A solution of diethyl 4-/4'-methylsulphinyl-2'-
(n-hexyl)-phenox ~-isophthalate (0.62 g) in polyphosphoric
acid (50 ml) was stirred at room temperature and sodium azide
(0.1 g) was added thereto in small portions. The mixture
obtained was stirred for one hour during which time it attained
a cream-like consistency and warmed to about 50 by heat of
reaction. The mixture was diluted with water and extracted
with ethyl acetate. The organic extract was washed with sodium
bicarbonate solution, then with water. Evaporation o~ the
solvent gave diethyl 4-/4'-(S-methylsulphonimidoyl)-2'-(n-
hexyl)-phenoxy~-isophthalate as a yellow viscous oil (0.58 g,
91%).
I.R. Spectrum ~ ~NH = 3290 cm (sulphoximine NH)
~CO = 1730 cm 1 (ester CO)
N.M.R. Spectrum (CDC13)
1.48r (d,J = 2.5 EIz) - E]-2
3() 1.95,~ (q,J = 2.5 and 8.5 I-Iz) - Il-~
2.17~ (d,J = 2.5 E~z) - ~1-3'
2.31~ (q,J = 2.5 and 8.5 Hz) - EI-5'
-- 8 --
~Z6Z82
3.15~ (d,J = 8.5 Hz)
- H-5 and EI-6'
3.30L (d,J = 8.5 Hz)
5.66~ (q,J = 7.0 Hz)
- 2x/-o-cH2-cH3J
5.77L (q,J = 7.0 Hz)
6.967 (s) - -SO(NH)-CH3
7.32r (t,J = 7.0 Hz) - Ar-CH2-CH2
8 1 - 9.4~ (broad m) - -CH2-(CH2)4-CH3
8.63~ (t,J = 7.0 Hz) _ _
- 2x /-0-CH -CH J
8.78, (t,J = 7.0 Hz) 2 3
9.16L (t,J = 5.5 Hz) - CH3-CEI2
Step E : 7-(s-methYlsul~honimidov1)-5-(n-hexyl)-xanthone-2-
carboxylic acid
A solution of diethyl 4-/4'-(S-methylsulphonimido~l)-
~ 2'-(n-hexyl)-phenoxy ~-isophthalate (0.5 g) in polyphosphoric
'~ acid (30 ml) was stirred at 100-110 for one hour, then the
temperature was gradually increased to 150 and stirring was
continued for a further hour. The dark red/brown reaction
mixture thus formed was diluted cautiously with water and
extracted with ethyl acetate. The organic extract was washed
well with water then evaporated giving 7-(S-methylsulphonimidoyl)-
5-(n-hexyl)-xanthone-2-carboxylic acid as a buff crystalline
solid (0.35 g, 83%). The produ-t was recrystallized from
ethanol, with charcoaling, as a white crystalline solid (MPt
194-6)
I.R.Spectrum ~ ~NH = 3270 cm (sulphoximine NII)
r ~CO = 1725 cm 1 (C02H), 1685 cm
(xanthone C0).
N.M.R. Spectrum (d6 - DMS0)
1.28~ (d,J = 2.5 Hz) - I-I-l
1.42l (d,J - 2.5 Hz) - H-8
1.61, (q,J = 2., and 8.5 E~z) - 11-3
1.74~ (d,J - 2.5 Hz) - EI-6
g
1~26282
.
2.20L (d,J = 8.5 Hz) - H-4
6.84~ (s) - SO(NH)-C~13
7.01~ (t,J = 7.5 Hz) - Ar-CH2-CH2
8-0 - 9.4~ (broad m) - -CH2-(CH2)4-CH3
9.13-~ (t,J = 5.5 Hz) - CH3-CH2
EXAMPLE 2
7-(S-Methylsul~honimido~1)-5-(n-hexYl)-xanthone-2-carboxylic
acid from diethyl 4-/4'-methylsulphinyl-2'-(n-hexyl)-phenoxy~-
isophthalate
10A solution of diethyl 4-/4'-methylsulphinyl- 2 1- ( n-
hexyl)-phenoxy~ -isophthalate (1.0 g) in polyphosphoric acid
(100 ml) was stirred in an atmosphere of dry nitrogen and was
maintained at ca 40 while sodium azide (0.16 g) was added
thereto in small portions. The resultant mixture was stirred
' for one hour during which period the o~iginal clear solution
became white opaque in appearance. The reaction mixture was
then stirred for a further 1/2 hour at room temperature before
being plunged into an oil bath at 150 and stirred until the
white opaque solution has changed to a clear brown colour (about
1 hour). The still warm reaction mixture was then diluted
carefully with ice-water and heated for ca 4 hour on a steam
bath. After being cooled the resulting mixture was extracted
with chloroform (2 x 100 ml). The chloroform extract was
~washed with water, then dried over magnesium sulphate, with
filtering out of a small amount of insoluble tar. The extract
;~was then evaporated leaving a pale yellow solid (0.7 g). This
material was recystallised from ethanol, with charcoaling,
to give 7-(s-methylsulphonimidoyl)-5-(n-hexyl)-xanthone-2-
carboxylic acid (0.64 g) as a white crystalline solid (m.pt.
193-5), identical with an authentic sample.
.-- 10 --
., ,
~',,,'-.~
