CA1126282A - Process for the preparation of xanthone derivatives - Google Patents
Process for the preparation of xanthone derivativesInfo
- Publication number
- CA1126282A CA1126282A CA322,692A CA322692A CA1126282A CA 1126282 A CA1126282 A CA 1126282A CA 322692 A CA322692 A CA 322692A CA 1126282 A CA1126282 A CA 1126282A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- carbon atoms
- alkyl radical
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
- C07D311/86—Oxygen atoms, e.g. xanthones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
Abstract
ABSTRACT OF THE DISCLOSURE:
A process for the preparation of xanthone der-ivatives of general formula I:
(I) wherein R represents a hydrogen atom or an alkyl radical containing 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:
A process for the preparation of xanthone der-ivatives of general formula I:
(I) wherein R represents a hydrogen atom or an alkyl radical containing 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:
Description
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, 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, ., 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 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.
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 .
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)
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, 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, ., 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 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.
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 .
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 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 ~
. ~ , 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' ~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 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 --., , ~',,,'-.~
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 ~
. ~ , 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' ~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 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 --., , ~',,,'-.~
Claims (8)
1. A process for the preparation of compounds of general formula I :
(I) wherein R represents a hydrogen atom or an alkyl radical containing 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, (II) wherein R and R1 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.
(I) wherein R represents a hydrogen atom or an alkyl radical containing 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, (II) wherein R and R1 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.
2. A process as claimed in claim 1, for the prepara-tion of compounds of general formula I wherein R represents a n-hexyl radical and R1 represents a methyl radical.
3. A process as claimed in claim 1, wherein cyclisa-tion is effected by means of a strong acid.
4. A process as claimed in claim 3, wherein the strong acid is polyphosphoric or concentrated sulphuric acid.
5. A process as claimed in claim 1, wherein the compound of formula II is obtained by reacting a compound of formula III:
(III) wherein R, R1, R2 and R3 are as defined in claim 1, with an alkali metal azide or with an 0-hydrocarbon-sulphonyl-hydroxyl-amine. 0
(III) wherein R, R1, R2 and R3 are as defined in claim 1, with an alkali metal azide or with an 0-hydrocarbon-sulphonyl-hydroxyl-amine. 0
6. Aprocess as claimed in claim 5, wherein the compound of formula III is obtained by reacting a compound of formula IV: 0 (IV) wherein R represents a hydrogen atom or an alkyl radical con-taining from 1 to 9 carbon atoms and R1 represents an alkyl radical containing from 1 to 5 carbon atoms, with a compound of formula V:
( V ) wherein R4 and R5, which may be the same or different, each represents an esterifying group and Hal represents a chlorine, bromine or iodine atom, in the presence of a weak base and of metallic copper or a copper oxide.
( V ) wherein R4 and R5, which may be the same or different, each represents an esterifying group and Hal represents a chlorine, bromine or iodine atom, in the presence of a weak base and of metallic copper or a copper oxide.
7, A process as claimed in claim 5, wherein the compound of formula III is obtained by esterifying a compound of formula VI :
( VI ) wherein R and R1 are as defined in claim 1, or a reactive derivative thereof with an appropriate alcohol.
( VI ) wherein R and R1 are as defined in claim 1, or a reactive derivative thereof with an appropriate alcohol.
8. A process as claimed in claim 6, wherein the compound of formula IV is obtained by oxidizing a compound of formula VII :
(VII) wherein R and R1 are as defined in claim 6.
(VII) wherein R and R1 are as defined in claim 6.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB859578 | 1978-03-03 | ||
| GB8595/78 | 1978-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1126282A true CA1126282A (en) | 1982-06-22 |
Family
ID=9855514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA322,692A Expired CA1126282A (en) | 1978-03-03 | 1979-03-02 | Process for the preparation of xanthone derivatives |
Country Status (9)
| Country | Link |
|---|---|
| CA (1) | CA1126282A (en) |
| CH (1) | CH639085A5 (en) |
| DK (1) | DK149853C (en) |
| ES (1) | ES478210A1 (en) |
| FI (1) | FI790686A (en) |
| FR (1) | FR2423487A1 (en) |
| LU (1) | LU80989A1 (en) |
| PT (1) | PT69303A (en) |
| SE (1) | SE445346B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL59046A (en) * | 1979-02-09 | 1985-03-31 | Roussel Uclaf | Process for the preparation of 7-sulfonimidoyl xanthone-2-carboxylic acid derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL47519A (en) * | 1974-07-09 | 1979-03-12 | Roussel Uclaf | 7-sulphinimidoyl(sulphimidoyl)-xanthone-2-carboxylic acid derivatives, their preparation and pharmaceutical compositions containing them |
-
1979
- 1979-02-01 SE SE7900889A patent/SE445346B/en not_active IP Right Cessation
- 1979-02-05 FR FR7902860A patent/FR2423487A1/en active Granted
- 1979-02-28 FI FI790686A patent/FI790686A/en not_active Application Discontinuation
- 1979-03-01 ES ES478210A patent/ES478210A1/en not_active Expired
- 1979-03-02 CH CH209779A patent/CH639085A5/en not_active IP Right Cessation
- 1979-03-02 LU LU80989A patent/LU80989A1/en unknown
- 1979-03-02 CA CA322,692A patent/CA1126282A/en not_active Expired
- 1979-03-02 PT PT6930379A patent/PT69303A/en unknown
- 1979-03-02 DK DK88679A patent/DK149853C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK149853B (en) | 1986-10-13 |
| FI790686A (en) | 1979-09-04 |
| FR2423487B1 (en) | 1983-01-14 |
| PT69303A (en) | 1979-04-01 |
| SE7900889L (en) | 1979-09-04 |
| DK149853C (en) | 1987-06-29 |
| ES478210A1 (en) | 1979-11-01 |
| CH639085A5 (en) | 1983-10-31 |
| LU80989A1 (en) | 1979-10-29 |
| SE445346B (en) | 1986-06-16 |
| FR2423487A1 (en) | 1979-11-16 |
| DK88679A (en) | 1979-09-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| USRE32518E (en) | Camptothecin derivatives | |
| US4130566A (en) | Process for producing 5-carboxy-2-acetylthiophene | |
| JP2002509926A (en) | Novel ascorbic acid derivative and preparation method thereof | |
| SU884572A3 (en) | Method of preparing lysergol derivatives | |
| CA1126282A (en) | Process for the preparation of xanthone derivatives | |
| US4424361A (en) | Process for preparing polycyclic triazoles used to inhibit allergic responses | |
| US5942628A (en) | Method for the preparation of sulfo-N-hydroxy succinimade salts | |
| SU880251A3 (en) | Method of preparing thiochromane derivatives or their salts | |
| CA1146571A (en) | Process for the preparation of xanthone derivatives | |
| US4086420A (en) | Thioprene or furan derivatives and process for preparation thereof | |
| JPH0867669A (en) | Sulfur compound | |
| Haworth et al. | 220. The constituents of natural phenolic resins. Part VII. Arctigenin | |
| US4153610A (en) | Process for producing 5-carboxy-2-acetylthiophene | |
| KR810001413B1 (en) | Process for preparing 2,3-dichloro-4-(2-thenoyl)phenoxy acetic acid | |
| KR810001695B1 (en) | Process for the preparation of terephthalamide derivatives | |
| RU2065440C1 (en) | Method for production of derivatives of 3-phenylthioanthra[1,9-cd]-isoxazol-6-on | |
| KR860000587B1 (en) | Process for preparing analgesic anti-inflammatory salicy acid derivatives | |
| JPH05170757A (en) | Production of tocopherol ester | |
| US4242267A (en) | Process for preparing 5-alkyl-7-(S-alkyl-sulfonimidoyl)-xanthone-2-carboxylic acids | |
| JPS6034551B2 (en) | Tetrahydroxanthone derivative | |
| JPS6019738B2 (en) | Novel anthranilic acid derivative | |
| PL165452B1 (en) | Method of obtaining novel quinollinic salt | |
| RU2072356C1 (en) | Method for production of derivatives of 5,6-phthalyl phenothiazine | |
| CA1254228A (en) | Method of producing the p-chlorophenol ester of p- chlorophenoxyisobutyric acid | |
| Klemm et al. | The insertion and extrusion of heterosulfur bridges. XIII. Syntheses and structural studies of nitrophenanthro [4, 5‐bcd] thiophenes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |