DK149853B - METHOD FOR PREPARING S-ALKYL-SULPHONIMIDOYLXANTHONE DERIVATIVES - Google Patents

Description

149853

The invention relates to a particular process for the preparation of known S-alkylsulfonimidoxylxanthone derivatives which can be used for the treatment of allergic conditions, which compounds have the general formula I according to the preamble of claim 1, and this process is characterized by the invention as defined in the characterizing part of the claim. .

The compounds of general formula I and methods of their preparation are described in English Patent Specification No. 1,518,083. As stated in this publication, the 10 'has interesting antiallergic properties and is particularly important in the treatment of allergic asthma and asthmatic bronchitis of allergic origin. According to the present invention, these compounds can be prepared in better yield and in fewer steps than in the prior art processes. Thus, the process 15 of the invention makes it possible to obtain the compound prepared according to Example 1 below from 2- (n-hexyl) -4- (methylthio) phenol in 5 steps versus 6 steps by the method of English Patent No. 1,518,083. In addition, the process of this invention yields a yield of approx. 3.2 times the yield according to the known method, calculated from the same starting compound.

Typically, R is preferably n-hexyl and R 6 is preferably methyl.

In connection with the general formula II as defined in the characterizing part 2 of the claim, R and R can e.g. each denotes an alkyl group containing 1-3 carbon atoms, an aryl group such as nitrophenyl, an aralkyl group such as nitrobenzyl or a dialkylaminoalkyl group such as dimethylarinoethyl. According to a 2

preferred embodiment are the esterifying groups R

3 and R are such as are capable of allowing compound II to be obtained in crystalline form to facilitate the preparation of the pure compound of formula II.

The cyclization of the compound of formula II is conveniently carried out by a strong acid such as e.g. polyphosphoric acid or concentrated sulfuric acid, in which case hydrolysis to free acid of formula I usually takes place at the same time or e.g. after addition of water. However, where one obtains the ester corresponding to the formula I ester, the free acid hydrolysis can be carried out in a separate step according to conventional methods. untrusted temperatures for cyclization are approx. 150 ° C.

The compound of formula II is obtained, if desired

occurred in situ, by reaction of a compound of formula III

5 ° _ ', \ R5OOC 9

^ -S V ^ / C00R

I A. XJ

10 TR

Wherein R, R, R and R are as defined in the claim with an alkali metal azide or with an O-hydrocarbon sulfonylhydroxylamine.

Preferred O-hydrocarbon sulfonylhydroxylamines are aromatic sulfonyloxy compounds, e.g. O-mesitylensul-fonylhydroxylamin. The reaction is conveniently carried out at room temperature and preferably in the presence of a chlorinated organic solvent, e.g. dichloromethane.

When an alkali metal azide is used, this is for stepwise sodium azide. Preferably, the reaction is carried out in an anhydrous acidic medium, e.g. in the presence of polyphosphoric acid and at temperatures between room temperature and 50 ° C. It will be understood that when the reaction is carried out in the presence of an acid, the product will be obtained in acidic solution, in which case - if the acid is a strong acid - cyclization and hydrolysis to form the desired compound of formula I may be carried out simply by heating. of the reaction mixture followed by addition of water.

The compound of formula III is prepared by reacting a compound of formula IV 0 R - ^ - Sv (iv)

35 I 'I

kx

. OH

R -

wherein R and Rx have the same meaning as defined in the claim, with a compound of formula V

149853 3 R? 0 ° CX ^ COOR * ^ XJJ (V)

Hal 2 3 wherein R and R have the same meaning as claimed in the claim, and Hal represents chlorine, bromine or iodine, in the presence of a weak base and metallic copper or a copper salt, preferably in the form of a powder. The weak base may e.g. be an alkali metal carbonate such as sodium or potassium carbonate.

In the process described in the aforementioned British Patent Specification No. 1,518,083, the phenolic component corresponding to compound IV carries an R 2 S group instead of an R 2 SO group and the oxidation is carried out after the coupling reaction. However, in this coupling reaction described previously, temperatures above 150 ° C decrease the yield of the coupling compound due to side reactions, although the coupling reaction itself proceeds better at higher temperatures. An advantage of the present process is therefore that the coupling reaction 15 can be carried out at higher temperatures, e.g. in the area

160-180 ° C, for example 170 ° C. The substituent Hal is preferably bromine. The compound of formula III is often difficult to purify as it is an oil and it may be advantageous to perform a hydrolysis, e.g. with an alkali metal hydroxide such as sodium or potassium hydroxide to form a compound of formula VI

ISLAND

1 «

Rt-S ^ v.H00C. ^ COOH

25 JhJ VI)

R

wherein R and have the same meaning as set forth in the claim, which compound of formula VI is then esterified by purification by crystallization with a corresponding alcohol to give the desired compound of formula III. Such a process can also be used when one wishes to change the esteri groups in III, e.g. for esterifying groups which allow for easier purification of the product due to the formation of a crystalline compound, or for esterifying groups which are sensitive to reactions used to prepare the compound of formula V and thus cannot be introduced previously.

If a residue redefining is carried out, the diacid or a reactive derivative thereof can be reacted with a corresponding alcohol. If the diacid itself is used, the reaction is preferably carried out in the presence of an acid or a carbodiimide reagent such as e.g. carbonyl diimidazole or dicyclohexyl arbodiimide. Where relatively compound esters are required, it may be convenient to convert the diacid to a reactive derivative thereof such as a diacid halide, f.

For example, by reacting with a reagent such as oxalyle chloride or thionyl chloride or bromide, followed by reaction with the alcohol.

The phenol of formula IV is prepared from one

phenol of formula VII

20 R? - S _ rx -

Y "OH

1 * 25 wherein R and fi have the same meaning as in claim 1j by oxidation, e.g. using a periodate such as sodium meta periodate or another peroxidizing agent. The section may e.g. is carried out in the presence of a low molecular weight alkanol as solvent and advantageously under reflux.

The following examples illustrate the process of the invention.

35 '149853

Example 1 7- (S-Methylsulfonimide oyl) -5- (n-hexyl) xanthone-2- carboxylic acid.

Step A; 2- (n-hexyl) -4- (methylaulfinyl) -phenol.

A solution of 2- (n-hexyl) -4- (methylthio) phenol 5 (2.24 g) in ethanol (50 ml) is heated under reflux and a solution of sodium metaperiodate (3.2 g) in water (20 g). ml) is added dropwise. The resulting mixture is stirred at reflux for an additional 30 minutes, then cooled, filtered and diluted with water. The resulting mixture is extracted with ether, evaporation of the ether extract gives 2- (n-hexyl) -4- (methylsulfinyl) phenol as a red oil (2.72 g, 100 $). The substance is obtained as a low melting white solid (m.p. 45.5 - 47 ° C) after ehromatography and low temperature crystallisation.

IR spectrum: 9Sq = 1020 cm ”" (1) (sulfide oxide-SO) oh oh = 3150 ΓπΓ1 (phenol-OH) NMB spectrum (ODCl ^): 2.58 δ (d, J = 2.5 Hz) - H-3 2.64 δ = 2.5 and 8.0 Hz) - H-3.0 3.0 T (d, J = 8.0 Hz) - H-6 7.27T (s) - -so- ch3 7.36T (t, J = 7.5 Hz) - Ar-CHg-OHg- 8.1 - 9.3 Γ (wide m) - -CH2- (CH2) 4 ~ CH5 9.13Γ (t, J = 5.5 Hz) - CH 3 -CH 2 Step B: 4- (4 ♦ -Methylsulfinyl) - (n-hexyl) -phenoxy) -isophthalic acid.

A solution of 2- (n-hexyl) -4- (methylsulfinyl) phenol (2.4g) and dimethyl-4-bromoisophthalate (2.73g) in dry nitrobenzene (20ml) is treated with copper powder (0.2 g) and potassium 3-oarbonate (2.8 g). The resulting mixture is stirred vigorously for 6 hours at 170-180 ° C under a stream of dry nitrogen.

The resulting black reaction mixture is cooled and treated with a solution of sodium hydroxide (1.6 g) in ethanol (22 ml) and water (8 ml). The mixture thus obtained is heated under reflux for an additional 1 hour to hydrolyze the diester. The reaction mixture is then cooled, diluted with water and the nitrobenzene extracted with dichloromethane. The residual aqueous extract is washed with dichloromethane, acidified with concentrated hydrochloric acid and re-extracted with chloroform. The organic extract is washed with water, dried over magnesium sulfate and evaporated to give 4- (4'-methylsulfinyl-2r- (n-hexyl) -phenoxy) -iso-phthalic acid as a dark red viscous gum or glass mass. The crude product is dried in vacuo and then ground in a mortar to a fine brown powder (2.84 g, 10? °) · HMR Spectrum (dg - DMSO): 1.58 r (d, J * 2.5 Hz) - Ξ -2.10 1.93τ (q, J = 2.5 and 8.5 Hz) - H-6 2.34 r (d, J = 2.5 Hz) - Η-3 »2.44r (q, J = 2.5 and 8.5 Hz) - H-5 '2.98? (d, J = 8.5 Hz) 3.05t (d, J = 8.5 Hz) "H" 5 ° SH "6 '7.26 τ (s) - SOOHj 7.37T (t, J = 7.0 Hz) - Ar-GHg-GHg-8.1 - 9.4τ (wide m) - -CH 2 -C 2 -9,201 (t, J = 5.5 Hz) - CH 1-4- (4 * -methylsulfinyl-2,3- (n-hexyl) phenoxy) -20 isophthalate.

A solution of 4- (4'-methylsulfinyl-2, - (n-hexyl) -phenoxy) -isophthalic acid (0.1 g) in ethanol (10 ml) is treated with 10 drops of concentrated sulfuric acid and the resulting solution is heated under reflux for 4 hours, then cool down and pour into water. The resulting solution is basified with sodium carbonate and then extracted with ethyl acetate.

The organic extract is washed with water and dried over magnesium sulfate, and the solvent is evaporated to leave diethyl 4- (4'-methylsulfinyl-2 '- (n-hexyl) phenoxy) isophthalate as a yellow viscous oil ( 0.1 g, $ 88). The product is obtained in a pure state by column chromatography on silica gel eluting with chloroform.

I, R, Spectrum: 9 CO = 1725 cm ”1 (ester-CO) 9 SO = 1050 ΤπΤ 1 (sulfide oxide-SO) HMR spectrum (CDCl ^): 1.39 ΐ (d, J = 2.5 Hz ) - H-2 1.88 τ (g, J = 2.5 and 8.5 Hz) - H-6 7 2.38 r (d, J = 2.5 Hz) - Η-3 »2, 57 T (q, J = 2.5 and 8.5 Hz) - H-5 * 3,107 (d, J = 8.5 Hz) 3.14 7 (d, J = 8.5 Hz) "H" 5 and H "6" 5 5.62 r (q, j = 7.0 Hz) 5.69 7 (q, J = 7.0 Hz) "+ (- OC2 -CH2) 7.29t (a) - SOCHj7 , 30r (t, J = 7.5 Hz) - Ar-CH 2 -CH 2 - 8.1 - 9.4 r (wide m) - -0 + - (CH J = 7.0 Hz) 8.73 7 (t, J = 7.0 Hz) 2x (-0-CH 2 -CH 5) 9.15 7 (t, J = 5.5 Hz) - CH 3 -CH 2

Irin D: Diethyl-4- (4 »- (S-methylsulfonimidovyl) - ^ - (n-hexyl) -phenosyl) -isphthalate.

A solution of diethyl 4- (4'-methylsulfinyl 1 - (n-hexyl) phenoxy) isophthalate (0.62 g) in polyphosphoric acid (50 ml) is stirred at room temperature and sodium azide (0 1 g) is added in small portions. The resulting mixture is stirred for 1 hour, during which time it reaches creamy consistency and is heated to about 50 ° 0 at its reaction heat. The mixture is diluted with water and extracted with ethyl acetate. The organic extract is washed with sodium bicarbonate solution and then with water. Evaporation of the solvent gives diethyl 4- (4, - (S-methylsulfonimidoyl) -2'-25 - (n-hexyl) phenoxy) isophthalate as a yellow viscous oil (0.58 g, 9 #).

IR spectrum: = 3290 cm -1 (sulfoxymine-HH) + co = 1730 cm -1 (eater "c °) IMR spectrum (CDO1 +): 1.48 T (d, J = 2.5 Hz) - H -2 1.95 * 7 (q, J = 2.5 and 8.5 Hz) - H-6 7.17 * 7 (d, J = 2.5 Hz) - H-3 '2.317 (q, J = 2.5 and 8.5 Hz) - H-5 '3.15Γ (d, J = 8.5 Hz) 3.30r (d, J = 8.5 Hz) "H" 5 and 5.66 Γ (q, J = 7.0 Hz) 5.77Γ M98S3 δ 6.96 T (s) - -SO (NH) -CH 5 7.32 τ (t, J = 7.0 Hz) - Ar-CH C ^ 8.1 - 9.4 r (wide m) - -0 ^ - (O¾) 4-CH3 8.63Γ (t, J = 7.0 Hz) δ 8.78 ΐ (t, J * 7.0 Hz ) 9.16 T (t, J = 5.5 Hz) - CH 2 -CH 3 Step E: 7- (S-Methylsulfonimide and the like) -5- (n-hex). vl) -xanthone-2-carboxylic acid.

A solution of thi 1-4- (4 · - (S-methylsulfonimide o-10 yl) -21- (n-hexyl) phenoxy) isophthalate (0.5 g) in polyphosphoric acid (30 ml) stirring at 100-110 ° C for 1 hour, then gradually increasing the temperature to 150 ° C, stirring is continued for an additional 1 hour. Bone dark red-brown reaction mixture is gently diluted with water and extracted with ethyl acetate. Bone organic extract is washed well with water and evaporated to give 7- (S-methylsulfonimidoyl) -5- (n-hexyl) -xanthone-2-carboxylic acid as a light brown crystalline substance (0.55 g, $ 83) " The substance is recrystallized from ethanol under treatment with activated charcoal as a white crystalline substance. Mp. 194-6 ° C.

I.R. Spectrum: 9m = 3270 cm -1 (sulfoxymine-NH) ή co = 1725 um-1 (OOgH), 1685 cm -1 (xanthone-CO) H.M.R. spectrum (dg-BMSO); 1.28 Γ (d, J = 2.5 Hz) - H1 1.42V (d, J = 2.5 Hz) - H-8 1.61 Γ (q., J = 2.5 and 8, 5 Hz) - H-3 1.74 7 (d, J = 2.5 Hz) - H-6 2.20 T (cb, J = 8.5 Hz) - H-4 6.84T (s) - SO (NH) -CH 5 7.01 T (t, J = 7.5 Hz) - Ar-C₂j-O₂ 8.0 - 9.4 Γ (wide m) - CH₂- (C ^) -CH ^ 9.137 (t, J = 5.5 Hz) - ^¾ -0.9 35 9 149853

Example 2.

7- (S-Methylsulfonimidoyl) -5- (n-hexyl) -xanthone-2-carboxylic acid from diethyl-4- (4'-methyllaulphinyl-2 '- (n-hexyl) -phenoxy) -alpha .

A solution of diethyl 1 -U'-methylsulfinyl 2 - - (n-hexyl) -phenoxy) -isophthalate (1.0 g) in polyphosphoric acid (100 ml) is stirred in an atmosphere of dry nitrogen and maintained at ca. . 40 ° C while adding sodium azide (0.16 g) in small portions. A resulting mixture is stirred for 10 hours, during which time the initially clear solution is milked. The reaction mixture is then stirred for an additional 30 minutes at room temperature before being dipped in an oil bath at 150 ° C and stirred until the milky solution changes to a clear brown color (about 1 hour). An even warm reaction mixture is then gently diluted with ice water and heated for approx. 15 minutes on steam bath. After cooling, the resulting mixture is extracted with chloroform (2 x 100 ml). The chloroform extract is washed with water and dried over magnesium sulfate, and a small amount of insoluble material is filtered off. The extract is evaporated to leave a pale yellow solid (0.7 g). Ethylene material is recrystallized from ethanol and treated with activated charcoal to give 7- (S-methylsulfonimidoyl) -5- (n-hexyl) -xanthone-2-carboxylic acid (0.64 g) as a white crystalline substance (m.p. 195 ° 0)> 25 which is identical to an authentic sample.

Claims (2)

A process for preparing S-alkylsulfonimidoyl-xanthone derivatives of the general formula I 0 0 5 if-s ^ I / s. R 2 represents a hydrogen atom or an alkyl group of 1-9 carbon atoms, and R 2 represents an alkyl group of 1-5 carbon atoms, characterized by oxidizing a 4- alkylthiophenol of the general formula VII r1'S'V ^ in T i (VII) 20 R upon which the resulting compound IV is reacted 25. II R: Ssy \ (l) (IV) T ^ H 30 with a compound of formula V R? OOCw ^ sXOOR?