GB2042540A

GB2042540A - Process for the preparation of xanthone derivatives

Info

Publication number: GB2042540A
Application number: GB8004291A
Authority: GB
Original assignee: Roussel Laboratories Ltd
Current assignee: Roussel Laboratories Ltd
Priority date: 1979-02-09
Filing date: 1980-02-08
Publication date: 1980-09-24
Also published as: ZA80141B; IL59046A0; AU531013B2; FI800392A; DK145948C; HU180552B; IE49389B1; AU5535080A; PT70795A; EP0016665A1; DK54180A; ES488385A0; IL59046A; ATE967T1; IE800250L; ES8102115A1; DK145948B; GB2042540B; JPS55108867A; EP0016665B1

Abstract

A process for the preparation of compounds of general formula I, <IMAGE> (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, <IMAGE> (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) followed if required, by hydrolysis to the free acid of formula I. The compounds of general formula I possess interesting anti-allergic activity.

Description

1 1 i 55

SPECIFICATION

Process for the preparation of xanthone derivatives This invention relates to a novel process for pre- 70 paring xanthone derivatives of interest in the treat ment of allergic conditions.

According to the present invention, there is pro vided a process for the preparation of compounds of general formula 1, 0 0 COOH N 1 10 U R (1) (wherein R represents a hydrogen atom or an alkyl radical containing from 1 to 9 carbon atoms and R, represents an alkyl radical containing from 1 to 5 carbon atoms) which comprises cyclising a com20 pound of formula It, 0 R,OOC, 11 1 '\ COOR 2 1 1---Q0 R 1 so 1 2 R Ar (11) (wherein R and R, 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) followed, if required, by hydrolysis to the free acid of formula 1.

The compounds of general formula 1 are described in our British Patent Specification No. 1,518,083. As indicated therein they possess interesting antiallergic 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 sulphonimidoyl groupings. In general, R preferably represents an n-hexyl radical and R, preferably represents a methyl radical. Ar preferably represents a monocyclic aryl group having 6 to 10 carbon atoms, e.g. a phenyl group which may carry substituents such as C1-4 alkyl groups e.g. methyl groups. The p-tolyl group is preferred.

In the compound of formula 11, R, 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. nitrobenzyi, group; or a dialkylaminoalkyl, e.g. dimethylaminoethy], group. According to a preferred embodiment the esterifying groups R, and R3 are such as to enable the compound of formula 11 to be obtained in a crystallised form so as to facilitate the preparation of pure compound of formula 11.

Cyclisation of the compound of formula 11 is conveniently effected by means of a strong acid such as, for example, polyphosphoric or concentrated sul- phuric acid, in which case hydrolysis to the free acid of formula 1 generally takes place simultaneously or, for example, on addition of water. Where, however, a corresponding ester andlor aryisulphonimidoyl derivative is the final product of the cyclisation reac- tion, hydrolysis to the free acid of formula 1 may take GB 2 042 540 A 1 place in a separate stage according to conventional methods, e.g. by heating in acidic or basic solution. Preferred temperatures for the cyclisation are from 100 to 150,C.

The compound of formula 11 may be obtained, if desired, by reaction of a compound of formula Ill, 0 N OH z 1 W 2 Ar R (III) (wherein R, R, and Ar are as hereinbefore defined) with a compound of formula IV, 3 OOQ"T,5 COOR 2 Hal (IV) (wherein R2 and R, 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, 0 R - 1 '.

N O-R 1 4 W-9 1 2 R Ar (v) (wherein R, R, and Ar are as hereinbefore defined and R4 represents an acyl group, for example a group of formula -CO-X where X represents an alkyl group containing from 1 to 3 carbon atoms or a phenyl group). 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 boiling point of the reaction mixture.

The compound of formula V may be formed, if 110 desired, by oxidation of a compound of formula VI, R, - -p 1 1 1 -R 4 bu- Is- 1 1 -1 11 1 2 R Ar (VI) (wherein R, R,, R4 and Ar are as hereinbefore defined) e.g. using a periodate such as sodium metaperiodate, preferably in the presence of ruthenium (IV) oxide, or a peroxide oxidising agent. The oxidation is preferably effected in the presence of an organic solvent forthe 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 V1 may itself be obtained, if desired, by reaction of a compound of formula Vii, 2 R 1- 5 -Q- O-R 4 R (VII) (wherein R, R, and R, are as hereinbefore defined) 70 with a reagent of the formula ArSO-N- cl ,11+ (where Ar has the above meaning and M represents an alkali metal atom) advantageously chloramine T 75 (2-tolyl-SO N- Cl- 2 Na+)' 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 VII may in turn be prepared, for example, by reaction of a compound of formua VIII, R 1-S -p- OH R (VIII) (wherein R and R, 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 V11 represents a group of formula -CO-X (where X is as hereinbefore defined) the acylating agent may be a compound of formula Z-CO-X (where Z represents a chlorine or bromine atom) or a compound of formula (X-CO)20. The reaction of the compound of formula Vill 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 - methylsulphonomidoyl)xanthone 2 carboxylic acid StepA: 2 - hexyl - 4 - (methylthio)phenylbenzoate A solution of 2 hexyl - 4 - (methylthio)phenol (75 g) in pyridine (225 mi) was stirred with benzoyl chloride (100 g) at room temperature for two hours. Water (450 mi) was then added thereto and the resu Itant mixture was stirred for 1 hour. The product thus formed was filtered off, washed with water and dried to give 2 - hexyl - 4 - (methylth io) phenyl benzoate (110 9, 100%) as a colourless, crystalline solid, m.p. 57-580. Step 8 2 - hexyl - 4 - (S - methyl - N - tosylsulphimidoyl) -phenyl benzoate The 2 - hexyl - 4 (methylthio)phenyl benzoate obtained in step A (50 9) was added over 15 min. to a stirred solution of chloramine-T (43 9) in isopropanol (1 L) at 50'C. After stirring for 15 min. the suspension obtained was filtered, cooled to O'C and crystallisation induced. The product thus formed was filtered off and dried to give 2 - hexyl - 4 - (S - methyl - N tosyisu 1 ph imodoyl) phenyl benzoate (63 g, 83%) as a colourless crystalline solid, m. p. 111-112'. Step C: 2 - hexyl - 4 - (S - methyl - N tosylsulphonimidoyl) -phenyl benzoate A solution of the 2 - hexyl - 4 - (S - methyl - N - GB 2 042 540 A 2 tosyisu 1 ph im idoyi) phenyl benzoate obtained in step B (50 g) in dichloromethane (250 mi) was stirred vigorously with ruthenium (R) oxide (100 mg) and aqueous sodium periodate (50 mi, 10% w/v). A pale green emulsion was formed which darkened considerably after a few minutes when the periodate had been consumed. The process was repeated with four successive quantities of aqueous sodium periodate (50 mi, 10% w/v), the time taken to reprecipitate the catalyst 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 (100 mi). The combined organic solutions were washed with water, dried (MgSO,) 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) - phenol The oil from the previous step was dissolved in methanol (250 m[) and the solution obtained was mixed with aqueous sodium carbonate (10%, 500 mi) and heated with stirring at 60'for 3 hours, where upon a clear solution was obtained. The solution was treated at room temperature with hydrochloric acid (20%, 100 mi) and the product thus formed extracted with chloroform. Evaporation of the sol vent under reduced pressure and trituration of the residue with 40-60 petrol gave 2 - hexyl - 4 - (S - methyl - N -tosyisulphonimidoyi)phenol (40 9,97% over two steps) as a colourless crystalline solid, m.p. 109-1100. Step E. ' dimethyl4 - [2 - hexyl - 4 - (S - methyl - N tosylsu lphon im idoyl)phen oxy] isophtha late A mixture of the 2 - hexyl - 4 - (S - methyl - N tosyisulphonimidoyi)phenol obtained in the previous step (20 g), dimethyl 4 - brompisophthalate (15 g), potassium carbonate (10 g), copper powder (1 g), nitrobenzene (100 mi) and tolbene (50 mi) was stirred under nitrogen and heated slowly io 16P'while some of the toluene (approx. 25 mi),was distilled out to dry the mixture. The temperature was maintained at 1600 for 2 hours and then the remainder of the solvent was distilled off under reduced pressure. The cooled residue was dissolved in dichloromethane (400 mi) and the solution obtained was filtered and evaporated under reduced pressure. The residue was dissolved in ether (250 mi) and induced to crysA tallise by cooling the solution obtained to C The solid was filtered off, washed with ether and dried to give dimethy14-[2- hexyl -4-(S -methyl - N tosyisulphonimidoyi)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. Step F.' 5 hexyl - 7 - (S - methylsulphonimidoyl)xanthone - 2 - carboxylic acid A solution of the dimethyl 4 - [2 - hexyl - 4 - (S - methyl - N - tosyisu lphonirn idoyl)phenoxy] isophtha- 1 1 t 3 GB 2 042 540 A 3 late obtained in the previous step (5 g) in concentrated sulphuric acid (25 mi) was heated at 120'for 1 hour, cooled a little and poured with vigorous stirring into water (250 mi). The solid thus precipitated 5 was filtered off, washed with water and recrystallised from methanol to give 5 - hexyl - 7 - (S - methylsulphonimidoyi)xanthone - 2 - carboxylic acid (2.5 g, 7 4. TY6). Example 2 5-Hexyl-7-(S-methylsulphonimidoyl)xanthone-2 7 carboxylic acid Step A: 2 - hexyl - 4 - (methylthio)phenyl acetate A solution of 2 - hexyl - 4 - (methylthio) phenyl (6.6 g) in pyridine (36 mi) and acetic anhydride (18 mi) was stirred overnight at room temperature and then 80 poured into water. The mixture obtained was extracted with ether. The organic extract was washed with dilute hydrochloric acid, sodium bicarbonate solution and finally with water then evapo- rated to dryness. 2 - Hexyl -4 - (methylthio)phenyl acetate was obtained as a pale yellow oil (7.45 g, 950/0). Step 8: 2 - hexyl - 4 - (S - methyl - N tosylsulphimidoyl) - phenyl acetate A solution of the 2 - hexyl - 4 (methylthio) phenyl acetate obtained in the previous step (5 9) and chloramine - T trihydrate (6.5 g) in dioxan (250 mi) and water (125 mi) 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 mi fractions. Fractions (3)-(6) gave pure 2 - hexyl - 4 - (S methyl - N - tosyisu lph im idoyi) 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 tosylsulphonimidoyl) - phenyl acetate A solution of the 2 - hexyl - 4 - (S - methyl - N - tosyisulphimidoyi)phenyl acetate obtained in the previous step (19) in dichloromethane (40 mi) was treated with a solution of sodium metaperiodate (1 g) in water and soluble ruthenium (N) oxide (5 mg). 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 -tosyisulphonimidoyl)phenyl acetate as a colourless viscous oil which solidified on cooling (0.88 9,851/o). Step D: 2 - hexyl - 4 - (S - methyl - N - tosylsul;, 55 phonimidoyl) -phenol A suspension of the oily 2 - hexyl - 4 - (S - methyl N - tosyisu lphonimidoyi)phenyl acetate obtained in the previous step (0.8 g) in saturated sodium carbonate solution (30 m[) and ethanol (15 mi) was stirred at 50'for 15 mins, after which time all the oil had dissolved. The resultant solution was poured into water, acidified with conc. hydrochloric acid and extratced with ether. Evaporation of the solvent gave 2 - hexyl - 4 - (S - methyl - N - tosyisu I- a white crystalline solid upon triturating with etherlpetrol (60-80') (0. 65 g, 90% m.p. 107-9'). Step E: dimethy14 - [2 -hexyl-4 - (S - methylNtosylsulphonimidoyl)phenoxy] - isophthalate A solution of the 2 - hexyl 4 - (S - methyl - N tosyisulphonimidoyi)phenol obtained in the previous step (0.4 g) and dimethyl brom oisophtha late (0.3g) in nitrobenzene (10 m]) was dried azeotropically by the addition and distillation of benzene. The resultant solution was treated with copper powder (50 mg) and anhydrous 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 -[2 - hexyl 4 - (S - methyl - N -tosyisulphonimidoyi) - phenoxy] - isophthalate (0.53 g, 900/o). 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 - tosyisulphonimidoyi) - phenoxy] - isophthalate obtained in the previous step (0.2 g) in polyphosphoric acid (4 mi) was stirred at 80'forten minutes and the temperature gradually increased to 120'. The resultant dark red viscous reaction mixture was stirred a further 1' 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 methyisulphonimidoyl) - xanthone - 2 carboxylate and the corresponding acid (shown by tic and NIVIR spectra). The ester was obtained pure by column chromatography on silica gel eluting with ethyl acetate and collecting 50 mi fractions. Fractions (9)-(12) gave the pure methyl 5 hexyl - 7 - (S methyisulphonimidoyl)xanthone - 2 - carboxylate as a white crystalline solid. Step G: 5 - hexyl - 7 - (S - methylsulphonimidoyl)xanthone - 2 - carboxylic acid A solution of methyl 5 - hexyl - 7 - (S - methyisu Iphonimidoyi)xafnthone - 2 - carboxylate obtained in the previous step (0.1 g) in ethanol (5 mi) and water (1 mi) was treated with 0.2 N sodium hydroxide solu- tion (2.7 mi) and the resultant mixture was refluxed for 1 hour. After cooling, the solution obtained was acidified with 2 N hydrochloric acid solution. 5 hexyl - 7 - (S methyisulphonimidoyi)xanthone - 2 carboxylic acid separated out as a white solid and

Claims

was filtered off and washed well with water. (0.09 9, 93%, m.p. 193-4% CLAIMS

1. A process for the preparation of compounds of general formula 1, 0 0 R COOH N R (I) phonimidoyi)phenol as a white oil which solidified to 130 (wherein R represents a hydrogen atom or an alkyl 4 GB 2 042 540 A 4 radical containing from 1 to 9 carbon atoms and R, represents an alkyl radical containing from 1 to 5 carbon atoms) which comprises cyclising a compound of formula 11, 0 R 3 00"" COOR 2 R S 00 1) S 0 2 R A r (II) (wherein R and R, are as defined above, A, repres ents an aryl group and R, and IR,, which may be the same or different, each represents an esterifying group) followed if required, by hydrolisys to the free acid of formula 1.

2. A process as claimed in claim 1 wherein R rep resents an n-hexyl radical.

3. A process as claimed in claim 1 orclaim 2 wherein R, represents a methyl radical.

4. A process as claimed in any preceding claim wherein, in the compound of formula It, Ar repres ents a monocyclic aryl group having from 6 to 10 carbon atoms.

5. A process as claimed in claim 4 wherein, in the compound of formula 11, Ar represents a phenyl 90 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 11, Ar represents a p-tolyl group.

7. A process as claimed in any preceding claim wherein in the compound of formula 11, R2and R3, which may be the same or different, 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 11, R2 and R3, which may be the same or different, each represents a nitropheny], nit robenzyl or dimethylaminoethyl group.

9. A process as claimed in any preceding claim 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 sul- phuric acid.

11. A process as claimed in any preceding claim wherein the cyclisation is effected at temperatures of from 100 to 1500C.

12. A process as claimed in any preceding claim in which the acid of formula 1 is formed by hydrolysis 115 during the cyclisation step or by addition of water.

13. A process asclaimed in anyof claims 1 toll in which the product of the cyclisation step is subjected to hydrolysis in a separate stage.

14. A process as claimed in any preceding claim wherein the compound of formula 11 is obtained by reaction of a compound of formula Ill, 0 R 1 - OH 1 S.Q 2 A r R (wherein R, R, and Ar are as defined in claim 1) with 65 a compound of formula IV, R 3 OOC"I, COOR 2 H- (IV) (wherein R, and R,, 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. 75

15. A process as claimed in claim 14 wherein the metallic copper or copper oxide is in the form of a powder.

16. A process as claimed in claim 14 or claim 15 wherein the weak base is an alkali metal carbonate. 80

17. A process as claimed in anyone of claims 14 to 16 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 anyone of claims 14 to 17 wherein the compound of formula III is obtained by hydrolysis of a compound of formula V, 0 R S N S 4 1 R S02 I I R Ar (V) (wherein R, R, and Ar are as defined in claim 1 and R4 represents an acyl group).

19. A process as claimed in claim 18 wherein, in the compound of formula V, R, 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 or claim 19 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 anyone of claims 17 to 21 wherein the hydrolysis of the compound of formula V is effected under reflux.

23. A process as claimed in anyone of claims 17 to 22 wherein the compound of formula V is obtained by oxidation of a compound of formula VI, R i- 1 - N R 1 -1 4 SO-P 1 2 R Ar (111) 125 1 (VI) (wherein R, R, and Ar are as defined in claim 1 and R, is as defined in claim 17).

24. A process as claimed in claim 23 wherein oxidation is effected by means of a periodate or a peroxide oxidising agent.

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 anyone of claims 23 to 25 wherein the oxidation is effected in the pres ence of a halogenated hydrocarbon as solvent.

27. A process as claimed in anyone of claims 23 GB 2 042 540 A 5 to 24 wherein the compound of formula V1 is obtained by reaction of a compound of formula V11, R - S 1 -Q O-R 4 R (VII) (wherein R and R, are as defined in claim 1 and R4!S as defined in claim 15) with a reagent of formula cl ArSO 2 N "-, i+ (wherein Ar is as defined in claim 1 and M represents 15 an alkali metal atom).

28. A process as claimed in claim 27 wherein the reagent of formula ischloramineT.

M-cla ArS02 --,,,+

29. A process as claimed in claim 27 or claim 28 wherein the reaction of the compound of formula VII with the reagent of formula ArSO 2 N 1-1 C1 -, l,- is effected in the presence of an alkanol as solvent.

30. A process as claimed in anyone of claims 27 to 29 wherein the compound of formula VII is obtained by reaction of a compound of formula VIII, R IS -p- 0II R (wherein R and R, are as defined in claim 1) with an appropriate acylating agent.

31. A process as claimed in claim 30 wherein the acylating agent is an acid halide or anhydride.

32. A process as claimed in claim 30 or claim 29 wherein the reaction of the compound of formula VIII with the acylating agent is effected in the presence of an anhydrous organic solvent.

33. A process for the preparation of compounds of general formula I as defined and claimed in claim 1 substantially as herein described.

34. A process for the preparation of compounds of general formula I as claimed in claim 1 substantially as herein described in Example 1 or Example 2.

35. Compounds of general formula I as defined in claim 1 whenever prepared by a process as claimed in any one of claims 1 to 34.

36. Each and every novel method, process, composition, and product herein disclosed.

Printed for Her Majesty's Stationery Office by The Tweeddale Press Ltd., Berwick-upon-Tweed, 1980. Published atthe Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.