FI69072C - SOM MELLANPRODUKTER ANVAENDA FOERENINGAR VID FRAMSTAELLNING AVETEROCYKLISKT SUBSTITUERADE 5-SULFAMOYLBENSOESYRADERIVAT - Google Patents

Description

69072 Compounds used in the preparation of heterocyclic-substituted 5-sulfamoylbenzoic acid derivatives as intermediates 5 Separated from patent application 751213

The invention relates to intermediates used in the preparation of heterocyclic-substituted 5-sulfamoylbenzoic acid derivatives of the formula I.

10 / "" Λ H2C iH2 ^ N ^

X I

x Tl NO, S '' COOR3 R1 / 2

The compounds of the invention have the general formula 20

A

Z = ί \ = Z

xn / 25 COOR 3 wherein A is a C 1 -C 4 hydrocarbon chain which may be substituted by halogen or C 1 -C 4 alkyl, is hydrogen or C 1 -C 4 alkyl, X is benzyl, phenoxy, phenylthio or anilino, wherein the phenyl ring may be substituted by halogen or C 1 -C 4 alkyl, and each Z independently represents two hydrogen atoms or one acid atom.

Compounds of general formula I are prepared as follows: 2 of general formula III 6 9072

- A

/ \ ch9 CH_ n -

5 I III

x 1 "(\ 3

Hal02S COOR

5-halosulfonylbenzoic acid derivatives according to the formula wherein R, A and X have the same meaning as above and Hal is a halogen atom are reacted with the formula: R1

HN

With an amine according to R 2 1 2 15, in which R and R have the same meaning as above.

The halosulfonylbenzoic acid derivatives of the formula III are obtained by various methods, e.g.

20 "χ C» 2 CH 2

OF

X J XX

25 A 3

H2N COOR

of aminobenzoic acid derivatives according to the Meerwein tun-2q reaction sequence described in J. pr. / 2/152, 251 (1939) or DBP 859 461.

The halosulfonylbenzoic acid derivatives are reacted in a manner known per se with the amines of the formula HNR1 35 1,2 11 3 69072 to give the final products of the formula I. The aminobenzoic acid derivatives of the formula XX are obtained by various methods, e.g. from the aminonitrobenzoic acid derivatives of the formula XXI known from the literature according to the reaction scheme X p "O10

iLL 1 / L - ^ X and H, XV

10 02NX \ COOR | () | ** XXI 0oN 3 2 000R3 o2n

XXII XXIII

15 by reacting the compounds with carboxylic acid derivatives of formula XVI as described above and then reducing the resulting compounds of formula XXII with hydrogen boron or complex borohydrides in the presence of a Lewis acid to the nitrobenzoic acid esters of formula XXIII. The nitro group is then preferably catalytically reduced by hydrogenation in the presence of Raney nickel or other conventional reduction agents.

Particularly preferably, compound XX can be prepared as follows:

A

Z ^ ^ COOH Z “V. 7 ° 1®2 \ 30 Y) ^ xY "> xx

/ V \ 3 f LL

H ~ N OOOR -i ^ 3

z I ^ N 'OOOR3 H2N COOR

XXIV

In the reduction of the 3-amido or 3-imido compounds of the formulas XXIII and XXIV, it is surprising that the reduction also takes place specifically in the presence of a nitro group.

4,69072

The following examples illustrate the invention.

Example 1 3- (1-Pyrrolidinyl) -4-phenoxy-5-sulfamoylbenzoic acid 5a) 3-N-Succinimido-4-phenoxy-5-nitrobenzoic acid methyl ester 105 g 3-Amino-4-phenoxy-5-nitrobenzoic acid methyl ester with mixed succinic anhydride (210 g) and stirring was continued for 2 hours with heating at 180 ° C.

The reaction mixture was stirred in 3 liters of water, and after some time extracted with methylene chloride. The organic phase was isolated, dried and evaporated. The residue was recrystallized from methanol in very good yield to give the desired compound, m.p. 152-154 ° C.

15 b) 3- (1-Pyrrolidinyl) -4-phenoxy-5-nitrobenzoic acid methyl ester

A solution of 44.4 g of the ester obtained in a) above in 300 ml of diglyme was reacted with boron trifluoride esterate (34 g) under a nitrogen atmosphere at 0 ° with stirring and then with a solution of 9.2 g of NaBH 4. In 200 ml of diglyme, keeping the temperature below + 15 ° C. After one hour, water was added dropwise. After completion of the exothermic reaction, 500 ml of water was added. The desired compound was then isolated in very good yield as orange needles, m.p. 118-120 ° C.

c) 3- (1-Pyrrolidinyl) -4-phenoxy-5-aminobenzoic acid methyl ester 30 g of the nitrobenzoic acid methyl ester obtained in b) dissolved in 500 ml of dioxane were catalytically hydrogenated with the addition of Raney nickel. After hydrogen uptake ceased, the mixture was filtered and the filtrate was evaporated. The residue was recrystallized from methanol in very good yield to give the desired product as colorless crystals, m.p. 153-156 ° C.

d) 3- (1-Pyrrolidinyl) -4-phenoxy-5-chlorosulfonyl-benzoic acid methyl ester 24.3 g of the amine ester obtained in c) dissolved in 150 ml of concentrated hydrochloric acid were cooled to -5 ° C and diazotized 5, With 46 g of NaNO 2 in 40 ml of water, whereby I! The temperature was kept below + 5 ° C. After 15 minutes, the light brown diazonium brine was stirred in a mixture of CuII chloride dihydrate (7.8 g), concentrated hydrochloric acid (24 mL) and saturated glacial acetic acid solution of SO 2 (200 mL) at 0 ° C. After gas evolution ceased, stirring was continued for a short time, then water was added to the reaction mixture, and the precipitated sulfochloride was extracted with methylene chloride. The organic phase was washed twice with water, dried and evaporated. From the residual oil 10 was obtained by adding diisopropyl ether in good yield the desired compound, m.p. 108-112 ° C.

e) 3- (1-Pyrrolidinyl) -4-phenoxy-5-sulfamoyl-benzoic acid methyl ester 25.0 g of the 5-chlorosulfonyl-benzoic acid methyl ester obtained in d) were added portionwise at room temperature with stirring to methylene chloride (150 ml) and 25% aqueous ammonia. the mixture was stirred for a further hour, the organic phase was separated, washed with water, dried over sodium sulphate and evaporated to dryness. The residual oil was recrystallized from methanol to give 5-sulfamylbenzoic acid ester in very good yield, m.p. 186-188 ° C. Saponification of the ester to 3- (1-pyrrolidinyl-4,4-phenoxy-5-sulfamylbenzoic acid is performed according to Example 5. mp 227-228 ° C.

Example 2 3- (1-Pyrrolidinyl) -4-phenoxy-5-sulfamoylbenzoic acid 30 a) 3- (1-Pyrrolidinyl) -4-phenoxy-5-nitrobenzoic acid 50 g 3- (1-pyrrolidinyl) -4 -phenoxy-5-nitro-benzoic acid methyl ester (Preparation: Example 34 35 step b) was saponified by heating with dilute sodium hydroxide solution. The orange-red solution was extracted twice with Cl 2 Cl 2, then the aqueous phase was acidified with concentrated hydrochloric acid. The desired acid is isolated as pale yellow crystals, m.p. 228-230 ° C.

b) 3- (1-Pyrrolidinyl) -4-phenoxy-5-aminobenzoic acid 5 32.8 g of the nitrobenzoic acid obtained in a) were dissolved in a solution of 8 g of NaOH in 200 ml of water, the solution was cooled to 0 ° C. , and a solution of sodium dithionite (90 g) in 380 ml of water was added, keeping the temperature below 10 ° C. The red-orange solution of Aluk-10 si turned pale yellow. The solution was stirred for a further hour without cooling, then acidified to pH 1 with concentrated hydrochloric acid and evaporated until crystallization began. The hydrochloride of the desired aminobenzoic acid was obtained as colorless crystals, m.p. 245-247 ° C.

If the dithionite contains sulphate, the corresponding sulphate is obtained as colorless crystals even before evaporation of the aqueous solution, m.p. 175-176 ° C.

Both give the corresponding amine, m.p. 100-103 ° C, 20 by neutralizing the aqueous solution to pH 4-4.5.

c) 3- (1-Pyrrolidinyl) -4-phenoxy-5-chlorosulfonylbenzoic acid

A solution of 8.35 g of the aminobenzoic acid hydrochloride prepared in b) in 25 ml of concentrated hydrochloric acid was diazotized at 0 ° C with a solution of 1.75 g of sodium nitrite in 15 ml of water, keeping the temperature below + 5 ° C. After 15 minutes, the diazonium solution was taken up in a stirred mixture of Cu dichloride dihydrate (2 g), concentrated hydrochloric acid (2 ml) and saturated SO2 glacial acetic acid solution (15 ml) cooled to 0 ° C. After completion of the foaming, stirring was continued for 30 minutes, then 150 ml of water was added to the reaction mixture, and it was extracted several times with ethyl acetate. The organic phase was washed, dried, evaporated, and addition of tl 69072 of ether and hexane to the residue gave crystalline sulfochloride, m.p. 163-165 ° C.

If aminobenzoic acid sulphate is used, the same sulphochloride is obtained in slightly worse yield.

5 d) 3- (1-Pyrrolidinyl) -4-phenoxy-5-sulfamoylbenzoic acid 7.6 g of the chlorosulfonyl derivative prepared in step c) are taken up in 15 ml of liquid ammonia. The ammonia is evaporated at room temperature and the residue is dissolved in a small amount of water. The solution is filtered and the pH is adjusted to pH 1 with concentrated hydrochloric acid. In this case, the desired sulfamylbenzoic acid precipitates as brownish crystals, from which pale yellow crystals are isolated by crystallization from a methanol / water mixture, m.p. 225 ° C.

Example 3 4-Phenoxy-3- (1-pyrrolidinyl) -5-dimethylsulfamoylbenzoic acid 7.2 g (0.02 mol) of 4-phenoxy-3- (1-pyrrolidin-20-yl) -5-sulfamoylbenzoic acid are dissolved in 100 ml. to 1N NaOH, and 10 ml of dimethyl sulfate are added to the solution. The mixture is stirred well at room temperature. After about 30 minutes, a white vaporous substance precipitates. It is filtered off with suction and heated with 2-N NaOH in a steam bath. When a clear solution is formed, it is allowed to cool and 4-phenoxy-3- (1-pyrrolidinyl) -5-dimethylsulfamoylbenzoic acid is precipitated with 2N HCl. The substance can be recrystallized from methanol / water. Yellow fibers are obtained, 30 m.p. 214-215 ° C.

Example 4 3- (1-Pyrrolidinyl) -4-phenoxy-5-sulfamoyl-benzoic acid a) 3,5-Dinitro-4-phenoxy-benzoic acid methyl ester 35 To 30 g of 3,5-dinitro-4-phenoxy-benzoic acid in 200 ml of methanol are added. 3 ml of concentrated sulfuric acid, and the mixture is boiled under reflux for 3 hours. After evaporation of the solvent, the residue is dissolved in ethyl acetate and traces of unreacted acid are removed with sodium bicarbonate solution. After drying the ethyl acetate solution, the solvent is evaporated and the residue is crystallized from ethyl acetate / methanol. The desired ester is obtained in very good yield. Sp. 171-173 ° C.

5 b) Methyl 3,5-diamino-4-phenoxybenzoate 25 g of 3,5-dinitro-4-phenoxybenzoic acid methyl ester are dissolved in 250 ml of ethyl acetate, 10 g of Raney nickel are added and hydrogenated. When the calculated amount of hydrogen is bound, the catalyst is filtered off, the solvent is removed, whereupon the residual oil crystallizes. The crude product can be used directly for further reactions, or it is recrystallized from a methanol / water mixture to give the diaminoester as colorless crystals in excellent yield, m.p. 140-142 ° C. Alternatively, the hydrogenation can also be performed in an autoclave at 50 ° C at 100 atm. The reaction time is then 3-5 hours depending on the activity of the Raney nickel.

c) 3-Succinylamino-4-phenoxy-5-aminobenzoic acid methyl ester 30 g of 3,5-diamino-4-phenoxybenzoic acid methyl ester in 300 ml of chloroform or methylene chloride were stirred at room temperature with succinic anhydride (12.8 g). hours when the desired benzoic acid methyl ester precipitated until colorless. The separated crystals were isolated and crystallized from methanol. 3-Succinylamino-4-phenoxy-5-aminobenzoic acid methyl ester was obtained as colorless crystals, m.p. 190-192 ° C.

d) 3- (1-Succinimido) -4-phenoxy-5-aminobenzoic acid methyl ester 30 g of 3-succinylamino-4-phenoxy-5-aminobenzoic acid methyl ester are introduced into a mixture of orthophosphoric acid (260 ml) and P 2 O 5 (60 g). , the mixture is heated to 50 ° C, then cooled and poured into 750 ml of water. The precipitated 3- (succinimido) -4-phenoxy-5-aminobenzo-35 acid methyl ester is isolated as colorless crystals in a quantitative yield of almost 69072 9, m.p. 200-201 ° C.

e) 3- (1-Pyrrolidinyl) -4-phenoxy-5-aminobenzoic acid methyl ester

To a solution of 24 g of 3- (1-succinimido) -4 -5 phenoxy-5-aminobenzoic acid methyl ester in 180 ml of diglyme is added 20 g of boron trifluoride etherate, and the solution is cooled to 10 ° C. A solution of 5.7 g of NaBH 4 in 125 ml of diglyme is added dropwise to the reaction mixture under cooling, so that the temperature must not rise above 10 ° C. After the addition is complete, stir for an additional hour, then carefully quench the reaction mixture with 300 mL of water. The precipitated solid is isolated and crystallized from methanol. Obtained in very good yield 3- (1-pyrrolidinyl) -4-phenoxy-5-amino-15-benzoic acid methyl ester, m.p. 154-156 ° C.

f) 3- (1-Pyrrolidinyl) -4-phenoxy-5-sulfamoyl-benzoic acid

The reaction sequence of Example 34 is repeated. The desired 3- (1-pyrrolidinyl) -4-phenoxy-5-sulfamylbenzoic acid methyl ester is obtained via the reaction with concentrated ammonia via 3- (1-pyrrolidinyl) -4-phenoxy-5-chlorosulfon-20-ylbenzoic acid methyl ester, m.p. 186-188 ° C, from which heating with sodium hydroxide and then acidification gives the desired 3- (1-pyrrolidinyl) -4-phenoxy-5-sulfamylbenzoic acid, m.p. 226-228 ° C.

Example 5 3- (1-Pyrrolidinyl) -4-phenoxy-5-sulfamylbenzoic acid The reaction sequence set forth in Example 4 is repeated to 3-succinylamino-4-phenoxyaminobenzoic acid. 10 g of 3-succinylamino-4-phenoxy-5-aminobenzoic acid ester are then stirred for 2 hours at 200 ° C. The reaction mixture is cooled, the separated crystals are recrystallized from methanol to give, in good yield, m 69072 10 3-succinimido-4-phenoxy-5-aminobenzoic acid methyl ester, m.p. 199-200 ° C.

The product obtained is converted as desired in Example 4 into the desired 3- (1-pyrrolidinyl) -4-phenoxy-5-sulfa-5-ylbenzoic acid, m.p. 227-228 ° C.

Example 6 3- (1-Pyrrolidinyl) -4-phenoxy-5-sulfamylbenzoic acid

The reaction sequence of Example 4 is repeated until step-10 sa e). 51 g of 3- (1-pyrrolidinyl) -4-phenoxy-5-amino-benzoic acid methyl ester are heated at reflux in 780 ml of 1N sodium hydroxide for 2 hours to give a clear solution. The reaction mixture is then cooled, the pH is adjusted to 4, and the precipitated product is dissolved in 50 ml of 2N HCl. After standing briefly, 3- (1-pyrrolidinyl) -4-phenoxy-5-aminobenzoic acid hydrochloride crystallizes out as comfy crystals, m.p. 254-257 ° C. Melting point with the product of Example 2 (step b): 252-254 ° C.

3- (1-Pyrrolidinyl) -4-phenoxy-5-aminobenzoic acid hydrochloride is converted to the desired 3- (1-pyrrolidinyl) -4-phenoxy-5-chlorosulfonylbenzoic acid as described in Example 2 above. -idinyl) -4-phenoxy-5-sulfamylbenzoic acid, m.p. 225-226 ° C.

Example 7 4-Phenoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid methyl ester 36.2 g of 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid are dissolved in 200 ml of methanol and ml of concentrated sulfuric acid and boil for 4-6 hours at reflux. On cooling, the ester crystallizes. Recrystallization from methanol, m.p. 191 ° C.

Example 8 4-Phenylsulfoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

A solution of 7.8 g of 4-phenylmercapto-3-69072 (1-pyrrolidinyl) -5-sulfamoylbenzoic acid in 130 ml of glacial acetic acid and 20 ml of 30% is stirred at room temperature. The progress of the reaction is monitored by thin layer chromatography. After 20 hours, the solution is poured into 5 x 800 ml of ice water. The precipitate is filtered off with suction, washed with water and dried. Crystallization from methanol / water gives 4-phenylsulfoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid as yellow crystals, m.p. 142-144 ° C (decomp.).

Example 9 4- (4'-Aminophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid 4- (4'-nitrophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid (18.5 g) dissolved in dimethyl-formamide is hydrogenated in the presence of Raney nickel at room temperature under normal pressure for 8 hours. The reaction mixture is filtered and 4- (4'-aminophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with water. Brown crystals are obtained, m.p. 234-240 ° C (dec.) 20 (crystallization from DMF / H 2 O) i The compound crystallizes with 1/2 mole of dimethylformamide, which cannot be removed even by prolonged heating at 120-150 ° C in vacuo.

Example 10 2 4- (4 * -Hydroxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid 9.5 g of 4- (4'-benzylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid are dissolved to water to which an equivalent amount of potassium hydroxy-30 dia has been added and hydrogenated in the presence of Raney nickel at 50 ° C under 100 atm in an autoclave for 5 hours. The mixture is filtered and 4- (4'-hydroxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with 2-hydrochloric acid (pH about 3). Crystallization from CH 2 OH / O 2 gives the product as pale yellow crystals, m.p. 12,69072 m.p. 271-273 ° C. NMR (D 6 -DMSO, 60 MHz, TMS) δ: 1.73 (quasi-s, 4H), 3.24 (quasi-s, 4H), 6.64 (quasi-s, 4H), 7.24 ( s, 2H), 7.58 (d, 1H), 7.88 (d, 1H), 9.0 (s, broad 1H).

Example 11 4-Phenylsulfonyl-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

A solution of 11.8 g (0.3 mol) of 4-phenylsulfinyl-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid in a mixture of glacial acetic acid (130 ml) and 30% hydrogen peroxide (20 ml), stirred at room temperature for about 30 hours. The reaction is monitored by thin layer chromatography (toluene / glacial acetic acid 4: 1). After completion of the reaction, the solution is added dropwise to ice water, the precipitate formed is filtered off with suction, washed with water and crystallized from CH 2 OH / O 2 mixture.

15 Yellow crystals are obtained, m.p. 170-172 ° C (dec.).

Example 12 4-Phenoxy-3-N-pyrrolidino-5-sulfamoylbenzoic acid 10 g of 3-N- (4-chlorobutylamino) -4-phenoxy-5-20 sulfamoylbenzoic acid methyl ester are added with stirring to 2-n sodium hydroxide. After a few minutes, a clear solution is obtained where 4-phenoxy-3- (2-oxo-1-pyrrolidinyl) -5-sulfamoylbenzoic acid is mixed by adding 2-n hydrochloric acid. Crystallization of the n-butano-25 list gives white crystals, m.p. 285-287 ° C (dec.).

The acid can be converted to the corresponding methyl ester by adding an equivalent amount of diazomethane in dimethoxyethane or diglyme, and the resulting methyl ester can be converted by reduction to 3-N-pyrrolidino-4-phenoxy-5-30 sulfamoylbenzoic acid methyl ester.

Example 13 4-Phenoxy-3- (1-pyrrodinyl) -5-benzyloxymethylsulfamoylbenzoic acid 11 g of 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid, 30 ml of a 40% formaldehyde solution 13 * 69072 and 100 ml of benzyl alcohol * are heated together at 100 ° C for 5 hours. The mixture is evaporated to dryness in vacuo and the residue is dissolved by heating with a small amount of acetonitrile. A crystalline product is obtained, m.p. 148-149 ° C.

5 <4 <

Claims (1)

In the preparation of heterocyclic-substituted 5-sulfamoylbenzoic acid derivatives of the formula I H2C. CH 2 (I) 1N 2 O 10 R 2 r NO ~ S '^' ^ x ^ \ C00R 12 in which R and R are the same or different and represent hydrogen or alkyl having 1 to 4 carbon atoms, 1 2 15 and R being hydrogen R may also be alkoxymethyl, phenoxymethyl or 3-phenylthiomethyl having 1 to 4 carbon atoms in the alkyl group, and R, X and A denote intermediates as defined below, characterized in that they have the formula 20 / A \ z = qc = z Wherein N is a C 1 -C 4 hydrocarbon chain which may be substituted by halogen or C 1 -C 4 alkyl, R 3 is hydrogen or C 1 -C 4 alkyl. , X is benzyl, phenoxy, phenylthio or anilino, wherein the phenyl ring may be substituted by halogen or C 1 -C 4 alkyl and each Z independently represents two hydrogen atoms or one oxygen atom.