PROCESS FOR THE PREPARATION OF XANTHONE DERIVATIVES

PROCEDE DE PREPARATION DE DERIVES DE LA XANTHONE

English Abstract

ABSTRACT OF THE DISCLOSURE:
The present invention relates to a process for the
preparation of compounds of general formula I,
<IMG> (1)
wherein R represents a hydrogen atom or an alkyl radical contain-
ing from 1 to 9 carbon atoms and R1 represents an alkyl radical
containing from 1 to 5 carbon atoms, which comprises cyclising a
compound of formula II,
<IMG> (II)
wherein R and R1 are as defined above, Ar represents an aryl group
and R2 and R3, which may be the same or different, each represents
an esterifying group and if required, hydrolysing the resulting
compound to obtain the corresponding free acid. The compounds of
general formula I possess interesting anti-allergic activity.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of compounds of general
formula I:
<IMG> (I)
wherein R represents a hydrogen atom or an alkyl radical contain-
ing from 1 to 9 carbon atoms and R1 represents an alkyl radical
containing from 1 to 5 carbon atoms ,which comprises cyclising a
compound of general formula II
<IMG> (II)
wherein R and R1 are as defined above, Ar represents an aryl group
and R2 and R3, which may be the same or different, each represents
an esterifying group and if required, by hydrolysing the resulting
compound to obtain the corresponding free acid.
2. A process as claimed in claim 1, wherein R represents
an n-hexyl radical.
3. A process as claimed in claim 1 or 2, wherein R1
represents a methyl radical.
4. A process as claimed in claim 1 wherein, in the
compound of formula II, Ar represents a monocyclic aryl group
having from 6 to 10 carbon atoms.
11

5. A process as claimed in claim 4 wherein, in the
compound of formula II, Ar represents a phenyl group optionally
substituted by one or more C1-4 alkyl groups.
6. A process as claimed in claim 5 wherein, in the
compound of formula II, Ar represents a p-tolyl group.
7. A process as claimed in claim 1 wherein in the
compound of formula II, R2 and R3, which may be the same or dif-
ferent, each represents an alkyl group containing from 1 to 3
carbon atoms or an aryl, aralkyl or dialkylaminoalkyl group.
8. A process as claimed in claim 7 wherein, in the
compound of formula II, R2 and R3, which may be the same or dif-
ferent, each represents a nitrophenyl, nitrobenzyl or dimethylamino-
ethyl group.
9. A process as claimed in claim 1, wherein cyclisation
is effected by means of a strong acid.
10. A process as claimed in claim 9, wherein the strong
acid is polyphosphoric or concentrated sulphuric acid.
11. A process as claimed in claim 1, 9 or 10, wherein
the cyclisation is effected at temperatures of from 100° to 150°C.
12. A process as claimed in claim 1, in which the acid
of formula I is formed by hydrolysis during the cyclisation step or
by addition of water.
13. A Process as claimed in claim 1, 9 or 10, in which
the product of the cyclisation step is subjected to hydrolysis
in a separate stage.
14. A process as claimed in claim 1, wherein the compound
of formula II is obtained by reacting a compound of general for-
mula III:
12

<IMG> (III)
wherein R, R1 and Ar are as defined in claim 1, with a compound
of general formula IV:
<IMG> (IV)
wherein R2 and R3 are as defined in claim 1 and Hal represents
a chlorine, bromine or iodine atom, in the presence of a weak
base and of metallic copper or a copper oxide.
15. A process as claimed in claim 14, wherein the metal-
lic copper or copper oxide is in the form of a powder.
16. A process as claimed in claim 14 or 15, wherein the
weak base is an alkali metal carbonate.
17. A process as claimed in claim 14, wherein
the reaction of the compound of formula III with the compound
of formula IV is effected under reflux.
18. A process as claimed in claim 14, wherein the com-
pound of formula III is obtained by hydrolysing a compound of
general formula V,
<IMG> (V)
13

wherein R represents a hydrogen atom or an alkyl radical containing
from 1 to 9 carbon atoms; R1 represents an alkyl radical containing
from 1 to 5 carbon atoms; Ar represents an aryl group and R4 re-
presents an acyl group.
19. A process as claimed in claim 18 wherein, in the
compound of formula V, R4 represents a group of formula -CO-X
where X represents an alkyl group containing from 1 to 3 carbon
atoms or a phenyl group.
20. A process as claimed in claim 18, wherein hydrolysis
of the compound of formula V is effected by means of an aqueous
solution of a weak base.
21. A process as claimed in claim 20, wherein hydrolysis
of the compound of formula V is effected by means of an aqueous
solution of an alkali metal carbonate.
22. A process as claimed in claim 18, 20 or 21, wherein
the hydrolysis of the compound of formula V is effected under
reflux.
23. A process as claimed in claim 18, wherein the compound
of formula V is obtained by oxidizing a compound of general for-
mula VI:
<IMG> (VI)
wherein R, R1, Ar and R4 are as defined in claim 18.
24. A process as claimed in claim 23, wherein oxidation
is effected by means of a periodate or a peroxide oxidising agent.
14

25. A process as claimed in claim 24, wherein oxidation
is effected by means of sodium metaperiodate in the presence of
ruthenium (IV) oxide.
26. A process as claimed in claim 23, 24 or 25, wherein
the oxidation is effected in the presence of a halogenated hydro-
carbon as solvent.
27. A process as claimed in claim 23, wherein the com-
pound of formula VI is obtained by reacting a compound of general
formula VII:
<IMG> (VII)
wherein R represents a hydrogen atom or an alkyl radical contain-
ing from 1 to 9 carbon atoms; R1 represents an alkyl radical con-
taining from 1 to 5 carbon atoms and R4 represents an acyl group,
with a reagent of formula
<IMG>
wherein Ar represents an aryl radical and M represents an alkali
metal atom.
28. A process as claimed in claim 27, wherein the reagent
of formula <IMG> is chloramine T.
29. A process as claimed in claim 27 or 28, wherein the
reaction of the compound of formula VII with the reagent of formula
<IMG> is effected in the presence of an alkano] as solvent.

30. A process as claimed in claim 27, wherein the com-
pound of general formula VII is obtained by reacting a compound
of general formula VIII:
<IMG> (VIII)
wherein R and R1 are as defined in claim 27, with an appropriate
acylating agent.
31. A process as claimed in claim 30, wherein the acylat-
ing agent is an acid halide or anhydride.
32. A process as claimed in claim 30 or 31, wherein
the reaction of the compound of formula VIII with the acylating
agent is effected in the presence of an anhydrous organic solvent.
16

Description

1~46571
This invention relates to a novel process for preparing
xanthone derivatives of interest in the treatment of allergic
conditions.
According to thc present invention, there is provided
a process for the preparation of compounds of general formula
I,
o
Rl-S ~ COOH (I)
~ ~ O
R
wherein R represents a hydrogen atom or an alkyl radical con-
taining from 1 to 9 carbon atoms and Rl represents an alkyl radical
containiny from 1 to 5 carbon atoms, which comprises cyclising a
compound of formula II,
o
" R OOC
~ ~ COOR2 (II)
S2
Ar
wherein R and Rl are as defined above, Ar represents an aryl group
and R2 and R3, which may be the same or different, each represents
an esterifying group and if required, hydrolysing the resulting
compound to obtain the corresponding free acid.
The compounds of general formula I are described in
British Patent Specification No. 1,518,083 in the name of the
applicants. As indicated therein they possess interesting anti-
allergic activity and are, in particular, of importance in the
treatment of allergic asthma and bronchial asthma of allergic
origin. According to the present invention, these compounds may
be prepared in good yields, using relatively stable intermediates
and avoiding the use of azides in the formation of the sulphonimi-
-1- ~

1~46571
doyl radicals. In general, R preferably represents an n-hexyl
radical and Rl preferably represents a methyl radical. Ar pre-
ferably represents a monocyclic aryl group having 6 to 10 carbon
atoms, ~.g. a phenyl group which may carry substituents such as
C1 4 alkyl groups e.g. methyl groups. The ~-totyl group is pre-
ferred,
In the compound of formula II, R2 and R3 may, for
example, each represent an alkyl group containing from 1 to 3
carbon atoms; an aryl, e.g. nitrophenyl group; an aralkyl, e.g.
nitrobenzyl group; or a dialkylaminoalkyl, e.g. dimethylamino~
ethyl, group. 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 crystallised form so as to facilitate the
preparation of pure compound of formula II.
Cyclisation of the compound of formula II is conveniently
effected by means of a strong acid such as, for example, poly-
phosphoric or concentrated sulphuric acid, in which case hydrolysis
to the free acid of formula I generally takes place simultaneously
or, for example, on addition of water. Where, however, a cor-
responding ester and/or arylsulphonimidoyl derivative is thefinal product of the cyclisation reaction, hydrolysis to the free
acid of formula I may take place in a separate stage according
to conventional methods, e.g. by heating in acidic or basic solu-
tion. Preferred temperatures for the cyclisation are from 100
to 150C.
The compound of formula II may be obtained, if desired,
by reacting a compound of formula III,
R1 S ~ (III)
.~
SO R
~r
--2--

1146571
wherein R, Rl and Ar are as hereinbefore defined, with a compound
of formula IV,
R 3OOC
COOR2
(IV)
Hal
wherein R2 and R3 are as hereinbefore defined and Hal represents
a chlorine, bromine or iodine atom, in the presence of a weak base
and of metallic copper or a copper oxide, preferably in the form
of a powder. The weak base may, for example, be an alkali metal
carbonate e.g. sodium or potassium carbonate. The reaction is
preferably effected under reflux.
The compound of formula III may be prepared, for example,
by hydrolysis of a compound of formula V,
O
Rl S ~ (V)
~ ~ 0-R4
N
SO2
Ar
wherein R, Rl and Ar are as hereinbefore defined and R4 represents
an acyl group, for example a group of formula -CO-X where X repre-
sents an alkyl group containing from 1 to 3 carbon atoms or a
phenyl ~roup. Hydrolysis is preferably effected by means of an
aqueous solution of a weak base such as, for example, an alkali
metal carbonate, e.g. sodium carbonate, and preferably at the boil-
ing point of the reaction mixture.
The compound of formula V may be formed, if desired, by
oxidation of a compound of formula VI,
Rl--S ~
~ ~ O-R4
S2 R (VI)
--3--

11~6S71
wherein R, Rl, R4 and Ar are as hereinbefore defined, e.g. using
a periodate such as sodium metaperiodate, preferably in the pre-
sence of ruthenium (IV) oxide, or a peroxide oxidising agent.
~- The oxidation is preferably effected in the presence of an organic
solvent for the compound of formula VI, such as, for example, a
halogenated hydrocarbon e.g. dichloromethane. Periodates will
normally be used in aqueous solution, in which case a 2-phase
solvent system may be present.
The compound of formula VI may itself be obtained, if
desired, by reacting a compound of formula VII,
Rl-S ~
R 0-R4 (VII)
wherein R, Rl and R4 are as hereinbefore defined, with a reagent
of the formula ArSO2N + where Ar has the above meaning and M
represents an alkali metal atom, advantageously chloramine T
Cl
(~-totyl-SO2N < +). The reaction is preferably effected in the
presence of an organic solvent, most preferably an alkanol such
as e.g. isopropanol.
The compound of formula VIJ may in turn be prepared,
for example, by reacting a compound of formula VIII,
Rl-S (VIII)
~ OH
wherein R and Rl are as hereinbefore defined, with an appropriate
acylating agent, for example an acid halide or anhydride. Thus,
for example when R4 in the compound of formula VII represents a
group of formula -CO-X wheLe X is as hereinbefore defined, the
acylating agent may be a compound of formula Z-CO-X where Z repre-

~6571
sents a chlorine or bromine atom, or a compound of formula(X-CO)2O. The reaction of the compound of formula VIII with the
acylating agent is preferably effected in the presence of an
anhydrous organic solvent such as, for example pyridine.
The following non-limiting Examples serve to illustrate
the invention.
Example 1
5-Hexyl-7-~S-meth~lsulphonomidoyl)xanthone-2~carboxylic acid
Step A: 2-hexyl-4-(methylthio)~henyl benzoate
_____ _________ ______ ___ __________
A solution of 2-hexyl-4-(methylthio)phenol (75 g) in
pyridine (225 ml) was stirred with benzoyl chloride (100 g~ at
room temperature for two hours. Water (450 ml~ was then added
thereto and the resultant mixture was stirred for 1 hour. The
product thus formed was filtered off, washed with water and dried
to give 2-hexyl-4-(methylthio)phenyl benzoate (110 g, 100 %) as
a colourless, crystalline solid, m.p. 57-58.
Step B 2-hexyl-4-(S-methyl-N-tosyls_l~h mldo~l)eh_nyl_b~a_oa~e
The 2-hexyl-4-(methylthio)phenyl benzoate obtained in
step A (50 g) was added over 15 min. to a stirred solution of
chloramine-T (43 g) in isopropanol (IL) at 50. After stirring
for 15 min. the suspension obtained was filtered, cooled to 0C
and crystallisation induced. The product thus formed was filtered
off and dried to give 2-hexyl-4-(S-methyl-N-tosylfulphimidoyl)
phenyl benzoate (63 g, 83%) as a colourless crystalline solid, m.p.
111-112.
Step C: 2-hexyl-4-~S-methyl-N-tosylsulphonlmidoyl)~henyl benzoate
A solution of the 2-hexyl-4-(S-methyl-N-tosylsulphimi-
doyl)phenyl benzoate obtained in step B (50 g) in dichloromethane
(250 ml) was stirred vigorously with ruthenium (IV) oxide (100 mg)
and aqueous sodium periodate (50 ml, 10% w/v). A pale green
emulsion was formed which darkened considerably after a few minu-

1146571
tes when the periodate had been consumed. The process was repeat-
ed with four successive quantities of aqueous sodium periodate
(50 ml, 10% w/v), the time taken to reprecipitate the cataIyst
increasing on each occasion. The total weight of sodium periodate
used was 25 g.
The organic layer was separated and the aqueous layer
extracted with dichloromethane (lO0 ml). The combined organic
solutions were washed with water, dried (MgSO4) and evaporated
under reduced pressure to give a colourless oil which was used
directly in the next step.
The catalyst may be recovered by filtering the reaction
mixture. The oil can be crystallised if required by trituration
in IMS to give a colourless, crystalline solid, m.p. 90-91.
steP D: 2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)~henol
The oil from the previous step was dissolved in methanol
(250 ml) and the solution obtained was mixed with aqueous sodium
; carbonate (lO~, 500 rnl) and heated with stirring at 60 for 3
hours, whereupon a clear solution was obtained. The solution was
treated at room temperature with hydrochloric acid (20%, lO0 ml)
and the product thus formed extracted with chloroform. Evaporation
of the solvent under reduced pressure and trituration of the
residue with 40-60 petrol gave 2-hexyl-4-(S-methyl-N- tosylsulpho-
nimidoyl)phenol (40 g, 97% over two steps1 as a colourless crys-
talline solid, m.p. lO9-110.
Step E: dimethyl 4- ~-hexyl-4-(S-methyl-N-tosylsul~honimidoylL-
E?henxYllsoE~hthalate
A mixture of the 2-hexyl-4-(S-methyl-N-tosylsulphonimi-
doyl)phenol obtained in the previous step (20 g), dimethyl 4-
bromoisophthalate (15 g~, potassium carbonate (lO g), copper powder
- (l g), nitrobenzene (lO0 ml) and toluene (50 ml) was stirred under
nitrogen and heated slowly to 160 while some of the toluene
--6--

6S~l
(approx. 25 ml) was distilled out to dry the mixture. The tem-
perature was maintained at 160 for 2 hours and then the remainder
of the solvent was distilled off under reduced pressure. The
cooled residue was dissolved in dichloromethane (400 ml) and
the solution obtained was filtered and evaporated under reduced
pressure. The residue was dissolved in ether (250 ml) and induced
to crystallise by cooling the solution obtained to 0. The solid
was filtered off, washed with ether,and dried to give dimethyl
4- ~2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)phenoxy~isophthalate
(15.7 g, 53~), as a light brown crystalline solid, m.p. 124-126 .
The filtrate was evaporated to dryness and the residue triturated
in 40-60 petrol to give a second crop of crude product (6.8g) in
need of further purification.
~E_~: 5-hexyl-7-1S-methylsulPhonimidoyl)xanthone-2-carboxyli~
acid
_ _ __
A solution of the dimethyl 4-L2-hexyl-4-(S-methyl-N-
tosylsulphonimidoyl)phenoxy~isophthalate obtained in the previous
step (5 g) in concentrated sulphuric acid (25 ml) was heated at
,120 for 1 hour, cooled a little and poured with vigorous stirring
into water (250 ml). The solid thus precipitated was filtered
off, washed with water and recrystallised form methanol to give
5-hexyl-7-(S-methylsulphonimidoyl)xanthone-2-carboxylic acid
(2.5 g, 74.9%).
ExamPle 2
5-hexYl-7-(s-methylsulphonimidoyl)xanthone-2-carboxylic acid
~E_~: 2-hexyl-4-~methylthio)phenyl acetate
A solution of 2-hexyl-4-(methylthio)phenol (6.6 g) in
pyridine (36 ml) and acetic anhydride (18 ml) was stirred overnight
at room temperature and then poured into water. The mixture
obtained was extracted with ether. The organic extract was washed
with dilute hydrochloric acid, sodium bicarbonate solution and

1~4~i571
~.
finally with water then evaporated to dryness. 2-hexyl-4-(methyl-
thio)phenyl acetate was obtained as a pale yellow oil (7.45 g,
95~).
Step B: 2-hexyl~4-(S-methyl-N-tosylsulehimidoyl)~henyl acetate
_____ ____ ______ ______-_ ____ __ ___ _ _ _ _________ ~
A solution of the 2-hexyl-4-(methylthio)phenyl acetate
obtained in the previous step (5 g) and chIoramine-T trihydrate
(6.5 g) in dioxan (250 ml) and water (125 ml) was stirred for five
hours, then evaporated to dryness leaving a red viscous oil (11 g).
The residue was chromatographed on a silica gel column eluting
with chloroform and collecting 50 ml fractions. Fractions (3)-
(6) gave pure 2-hexyl-4-(S-methyl-N-tosylsulphimidoyl)phenyl
acetate as a colourless viscous oil which solidified to a white
crystalline solid upon triturating with ice-cold petrol (60-80)
(5 g, 61~, m,p. 62-5).
steP C. 2-hexyl-4-~S-methyl-N-tosylsul~honimidoyl)~henyl acetate
_____ ____ ______ _______ ____ ________ _ ___ _________
A solution of the 2-hexyl-4-(S-methyl-N-tosylsulphimi-
doyl)phenyl acetate obtained in the previous step (l g) in dichlo-
romethane (40 ml) was treated with a solution of sodium meta-
periodate ~1 g) in water and soluble ruthenium (IV) oxide (5 mg)~20
The resultant mixture was stirred for 30 mins, then a further 5
mg of ruthenium oxide and 0.3 g metaperiodate were added thereto.
Stirring was continued for a further 15 mins, then the organic
layer was separated, filtered and evaporated to dryness. The
residue was chromatographed on a silica gel column eluting with
ethyl acetate. FractionS (2)-(3) gave pure 2-hexyl-4-(S-methyl-
N-tosylsulphonimidoyl)phenyl acetate as a colourless viscous oil
which solidified on cooling (0.88 g, 85~).
Step D: 2-hexyl-4-1S-methyl-N-tosylsul~honimidoylL~henol
A suspension of the oily 2-hexyl-4-(S-methyl-N-tosyl-
sulphonimidoyl)phenyl acetate obtained in the previous step (0.8 g)
in saturated sodium carbonat~ solution (30 ml) and ethanol (15 ml)

1~46571
was stirred at 50 for 15 mins, afterwhich time all the oil had
dissolved. The resultant solution was poured into waterl acidified
with conc. hydrochloric acid and extracted with ether. Evaporation
of the solvent gave 2-hexyl-4-(S-methyl-N-tosylsuphonimidoyl)
phenol as a white oil which solidified to a white crystalline solid
upon triturating with ether/petrol ~60-80; (0.65 g, 90% m.p.
107 9)
SteP E. dimethyl 4-12-hexyl-4-(S-methyl-N-tosylsul~honimidoylL-
____ __________ ___________ _ _____ ___ _ ______ _ _
phenoxy~-iso~hthalate
_____ _____ ________
A solution of the 2-hexyl-4-(S-methyl-N-tosylsulphoni-
midoyl)phenol obtained in the previous step (0.4 g) and dimethyl
bromoisophthalate (0.3g) in nitrobenzene (lO ml) was dried azeo-
tropically by the addition and distillation of benzene. The re-
sultant solution was treated with copper powder (50 mg~ and anhy-
drous potassium carbonate (0.4 g) and stirred for 2 hours at 160
under a stream of dry nitrogen gas. The mixture thus obtained
was cooled, diluted with chloroform, filtered and the solvent was
evaporated off under high vacuum leaving a red/brown viscous oil.
Trituration of the oil with petrol (60-80) caused it to solidify
to a buff crystalline solid which was the required dimethyl 4-L2-
hexyl-4-(S-methyl-N-tosylsulphonimidoyl)-phenoxy~-isophthalate
(0.53 g, 90~). The product was obtained as a white crystalline
solid after passage through a short silica gel column eluting with
chloroform (m.p. 115-7).
Step F- methyl-5-hexyl-7-(S-methylsulphonimidoyl)xanthone-2-
____ _______ ___________ ____ ________ _____________
carboxylate
_ _ _ _ _ _ _ _ _ _
A solution of the dimethyl 4-~2-hexyl-4-(S-methyl-N-
tosYlsulphonimidoyl)-phenoxy~-isophthalate obtained in the previous
step (0.2 g) in polyphosphoric acid (4ml) was stirred at 80 for
ten minutes and the temperature gradually increased to 120. The
resultant dark red viscous reaction mixture was stirred a further

1~46571
1 1/2 hours at 120 and then cooled and poured into water to give
a yellow viscous oil which was extracted into ethyl acetate.
The product thus obtained (0.11 g) was a mixture of methyl 5-hexyl-
7-(S-methylsulphonimidoyl)-xanthone-2-carboxylate and the corres-
ponding acid (shown by tlc and NMR spectra). The ester was obtained
pure by column chromatography on silica gel eluting with ethyl
acetate and collecting 50 ml fractions. Fractions (9)-(12) gave
the pure methyl 5-hexyl-7-(S-methylsulphonimidoyl)xanthone-2-car-
boxylate as a white crystalline solid.
SteP G: 5-hexyl-7-lS-methylsulphonimidoyl)xanthone-2-carboxyllc
acid
_ _ _ _
A solution of the methyl 5-hexyl-7-(S-methylsulphonimi-
doyl)xanthone-2-carboxylate obtained in the previous step~(0.1 g)
in ethanol (5 ml) ans water (1 ml) was treated with 0.2 N sodium
hydroxide solution (2.7 ml) an~ the resultant mixture was refluxed
for 1 hour. Afker cooling, the solution obtained was acidified
with 2 N hydrochloric acid solution. 5-hexyl-7-(S-methylsulphoni-
midoyl)xanthone-2-carboxylic acid separated out as a white solid
20 and was filtered off and washed well with water. (0.09 g, 93~,
m.p. 193-4).
--10--