CH630350A5 - Process for the preparation of aromatically substituted sulphamoylbenzoic acid derivatives. - Google Patents

Description

The invention relates to a process for the preparation of aromatically substituted sulfamoylbenzoic acid derivatives of the formula I.

R

35

Ì

(iii)

40 in which Y is halogen and R2 and ie ^ Ar ^ di have the meanings given, in the presence of copper powder to give compounds of the formula IV

, 2nd

45

50

N,

VR5

= no

55 in which the residues R1 to R5 and

(I)

@ di the above meaning in the

^ Ar ^ ei a mono- or bicyclic aromatic car-

bocyclic or heterocyclic ring system, R1 an alkyl group with 1 to 4 carbon atoms, R2 hydrogen or, substituted one or more times in the various positions, halogen, alkyl or alkoxy groups with 1 to have, and the compounds of the formula IV reduced .

The invention further relates to a process 60 for the preparation of aromatically substituted sulfamoylbenzoic acid derivatives of the formula I '

65

630 350

4th

b'n02s in the

©

io a mono- or bicyclic aromatic car-

bocyclic or heterocyclic ring system, R1 'hydrogen, R2 hydrogen or, substituted one or more times in the various positions, halogen, alkyl or alkoxy groups with 1 to 3 carbon atoms, 3,4-methylenedioxy, benzyloxy, -N02, -C = N , OH, formyl, acetyl or a carboxylic ester function -COOR, in which R represents an alkyl radical, and B 'represent two hydrogen atoms, which is characterized in that 3-nitro-4-halogeno-benzoic acid derivatives of the formula II

where R1, R2 and © have the meanings given above and B the protective group

15

20th

r-

= c - n,

r \

/ R \

\,

NR3

= no coor

(ii) 1

in which X is chlorine, bromine or iodine, R1 is an alkyl group having 1 to 4 carbon atoms and R3, R4 and R5 are the same or different lower alkyl groups, R3 can also be a hydrogen atom, and / or two of the substituents R3, R4 or R5 can also be cyclically linked to one another with compounds of the formula III

R

(III)

in which Y is halogen and R2 and ie © di have the meanings given, in the presence of copper powder to give compounds of the formula IV

r2 n02

\ 1

\ r5 /

in which R3, R4 and R5 represent identical or different lower alkyl groups, R3 can also represent a hydrogen atom, and / or two of the substituents R3, R4 or R5 can also be cyclically linked to one another,

acidic or alkaline hydrolyzed.

The preparation of the starting materials of the formula II is described in 30 of DE-OS 2 461 601.

From the literature (e.g. Jerry March, Advanced Organic Chemistry Mc Graw-Hill Book 'Company and Kogakusha Company LTD 1968, p. 508) it is known that compounds containing S02NH2 groups can be condensed with 35% copper powder (Ullmann- Reaction) are not accessible because side reactions take place that prevent the desired biaryl synthesis.

Surprisingly, on the other hand, the compounds of the formula II, in which the sulfonamide group is blocked by the protective group B, can be reacted with aryl halides of the formula III in the presence of fine copper powder in the manner of a Ullmann reaction in very good yields into the biaryl derivatives of the formula IV.

The formation of biaryl under the relatively harsh conditions 45 of the Ullmann reaction is even promoted by the sulf amoyl groups protected in this way. The good yields and the very specific course of the reaction indicate an autocatalysis, caused by a possible internal complexation of the intermediate Cu-organic compound by the basic N atom of the protective group and thus a stabilization of this intermediate.

As protection group B

NR3

n -

55

r

3rd

= no oor

(IV) 1

= c - n;

r \

60

n? 5 '

H

in which the radicals R1 to R5 and © have the meaning given above, and the compounds of the formula IV are reduced and, before the reduction of the nitro group, the compounds of the formula IV or after reduction of the nitro group, the compounds of the formula I.

preferably the remainder = C — N;

CH,

CH,

65

Compounds in which the substituents R3, R4 and R5 have the following meaning are also suitable:

5

630350

r3

r4

r5

ch3

ch3

ch3

h c2h5

qh5

c4hg ch3

ch3

h ch3

ch3

h ch3

C2hs-

-ch2-ch2-ch2-

ch3

chs

-ch2-ch2ch2ch2-ch2-

As an aryl group

©

preferably a benzene or naphthalene ring or a heterocyclic ring system is a 5- or 6-membered heteroaryl ring such as thiophene, pyridine, pyrimidine, thiazole, pyrazole, pyrazine, pyridazine, quinoline and isoquinoline.

In compounds of the formula III, Y preferably denotes an iodine or bromine atom as the halogen atom.

The processes according to the invention are normally carried out in such a way that the starting compounds of the formulas II and III are reacted together with the copper powder at temperatures between 50 to 200 ° C., preferably 150 to 200 ° C. in the melt or in an inert high-boiling solvent. In some cases the copper powder can be added immediately, in other cases only when the reaction temperature has been reached. If the reaction is carried out in the melt, it is useful to use nitrogen or another inert gas as the protective gas. The following higher-boiling organic solvents have proven particularly suitable as solvents: dimethylformamide, dimethylacetamide, tetramethylurea, N-methyl-pyrrolidone.

However, solvents such as dimethyl sulfoxide, sulfolane, hexamethylphosphoric trisamide, pyridine, quinoline or various higher-boiling aromatic, aliphatic and alicyclic hydrocarbons are also suitable. The metallic copper is normally used as the finest copper powder available for purchase. However, it can be activated beforehand by washing the commercially available copper powder with a 0.02 molar aqueous solution of the disodium salt of ethylenediaminetetraacetic acid or treating it with iodine.

The copper powder is mostly used in excess. When using a solvent, a small excess (10-20%) is often sufficient. In contrast, a two to five-fold excess is usually advantageous in the melt. The copper powder can also be used in combination with copper salts e.g. Copper (I) halides or Cu20 can be used.

The nitro group can be converted into the amino group using the methods customary in the literature, e.g. by catalytic hydrogenation with hydrogen and Raney nickel as a catalyst. But you can also use the common precious metal catalysts such as Use palladium on carbon or platinum oxide.

The catalytic hydrogenation is carried out in a manner known per se (e.g. Organikum S 271-277, pp. 507-510). The reaction takes place in a solvent in the presence of a catalyst. Organic solvents such as e.g. Methanol, ethanol, ethyl acetate, dioxane or other polar solvents, especially amides such as dimethylformamide or dimethylacetamide or with B '= 2 H and R1' = H also aqueous solutions of the alkali salts.

Hydrogenation is generally carried out at room temperature and under normal pressure or at elevated temperature and pressure, e.g. 50 ° C and 50 atm in an autoclave.

The intermediates of the formula IV obtained after the Ullmann reaction can be hydrolyzed before or after the reduction of the nitro group with elimination of the protective group B and the ester radical R1, with either alkaline, e.g. hydrolyzed with dilute alkali or alkaline earth hydroxides or acidic, with dilute inorganic acids. To prepare esters of the formula I in which B is two hydrogen atoms, the hydrolysed compounds of the formula I (R1 = H) obtained by the process according to the invention can then be esterified in a conventional manner with lower aliphatic alcohols.

A large number of substituted diaryl compounds can be prepared by the processes according to the invention, 20 of which some are mentioned below.

3-Amino-4- (4'-methylphenyl) -5-N, N-dimethylaminomethylene aminosulfonyl benzoic acid methyl ester

3-Amino-4- (5-methyl-2-thienyl) -5-N, N-dimethyIamino-methylenaminosulfonyl-benzoic acid methyl ester 25 3-Amino-4- (5-formyl-2-thienyl) -5-N, N- dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester

3-Amino-4- (2-thiazolyl) -5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester

3-Amino-4- (6-methyl-2-pyridyl) -5-N, N-dimethylamino-30 methyleneaminosulfonylbenzoic acid methyl ester

3-Amino-4- (3-pyridyl) -5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester

3-Amino-4- (2-pyridyl) -5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester

35

A large number of sulfamoyl-substituted diaryl compounds can be prepared with the aid of the processes according to the invention. The compounds of the formulas I and I 'are valuable intermediates for the synthesis of medicaments, 40 in particular diuretics and saluretics. For example, the

Compounds of the formulas I and I 'in which © = Phe-

nyl means serve as starting products for the synthesis of diurally-45 and saluretically active sulfamoylbenzoic acid derivatives, as described in German Offenlegungsschrift 24 42 69 6.

50

55

60

example 1

3-Amino-4-phenyl ~ 5 ~ N, N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester a) 3-Nitro-4-phenyl-5-N, N-dimethylaminomethylenami-65 nosulfonyl-benzoic acid methyl ester

70 g (0.2 mol) of 3-nitro-4-chloro-5-N, N-dimethylamino-methylenaminosulfonyl-benzoic acid methyl ester are mixed with 50 g of the finest copper powder and 100 g of iodobenzene

63035 »

6

admitted. The mixture is heated to 170-180 ° C. under an N2 atmosphere and well stirred and the melt is held at this temperature for about 2.5 hours. It gradually becomes thick and a thoroughly brown porridge forms. Excess iodobenzene is then distilled off and the residue is digested with n-hexane. The remaining rock-hard mass is dissolved in acetone, filtered from copper and copper halides and the solution evaporated. The remaining oil is digested twice with isopropyl ether or petroleum ether, dissolved in glacial acetic acid and dropped into ice water with vigorous stirring. A yellow substance flocculates. It is separated off, washed well and dried at 50 ° in vacuo. Crude yield (only slightly contaminated) 70 g recrystallization from CH3OH.

Yield 64.4 g - 82%

Light yellow needles with a melting point of 145-146 ° C

The reaction can also be carried out in dimethylformamide or tetramethylurea as a solvent.

b) 3-Amino-4-phenyl-5-N, N-dimethylaminomethylenamino-nosulfonyl-benzoic acid methyl ester

40 g of the nitro compound (Ia) are dissolved in ethyl acetate and hydrogenated with Raney nickel as catalyst for 2 hours at room temperature and normal pressure in the shaking duck. The mixture is then filtered, the residue is washed several times with acetone and the filtrate is concentrated. Recrystallization from CH3OH / a little acetone yield 34.6 g,

colorless crystals of mp 189-190 ° C Example 2

ooh h2n ° 2s

3-Amino-4-phenyl-5-sulfamoyl-benzoic acid a) The 3-nitro-4-phenyl-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester (1 a) is refluxed with 2N NaOH until a clear one Solution has arisen.

The 3-nitro-4-phenyl-5-sulfamoyl-benzoic acid is precipitated in the cold with 4N HCl and recrystallized from hot water.

Yellow crystals of mp. 209-211 ° C

The amino compound is obtained by catalytic hydrogenation with Raney nickel in dimethylformamide.

b) The 3-amino-4-phenyl-5-N, N-dimethylaminomethy-lenaminosulfonyl-benzoic acid methyl ester (1 b) is saponified and precipitated as described under (2 a).

Recrystallization from water

Mp 244-246 ° C

Example 3

3-amino-4- (4'-methoxyphenyl) -5-N, N-dimethylaminomethyl-lenaminosulfonyl-benzoic acid methyl ester nh,

10th

15

ooch.

ch.

kn-c = no_s / H

a) 3-Nitro-4- (4'-methoxyphenyl) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester

35 g (0.1 mol) of 3-nitro-4-chloro-5-N, N-dimethylamino

20 methyl methylenaminosulfonyl benzoates are mixed with 36 g iodanisisole (-0.15 mol) and 20 g finest copper powder and heated under nitrogen. At about 180 ° C the reaction starts quite abruptly and the temperature has to be kept between 180-200 ° C by cooling.

25 After the melt has solidified into a thick paste, the mixture is cooled, the solid mass is boiled out with acetone, filtered, the filtrate is evaporated and the residue is mixed with methanol. When standing overnight, the product crystallizes out.

30 yield 19 g

Recrystallization from ethanol mp 178-180 ° C

b) The nitro compound (3 a) is dissolved in ethyl acetate and with Raney nickel as a catalyst at room temperature

35 and normal pressure in the shaking duck were hydrogenated (taking up 1 hour of hydrogen). The mixture is then filtered, the filtrate is concentrated and the residue is recrystallized from CH3OH / a little acetone.

Colorless crystals with a melting point of 212-213 ° C

40

Example 4

3-A mino-4- (2-thienyl) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

45

50

55

nh,

cooch.

a) 3-Nitro-4- (2-thienyl) -5 ~ N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester

70 g of 3-nitro-4-chloro-5-N, N-dimethylaminomethylene-60 aminosulfonyl-benzoic acid methyl ester, 60 g of the finest copper powder and 100 g of 2-bromothiophene are mixed well and heated at 180 ° under a nitrogen atmosphere for 6 hours.

Then let it cool and digest several times in the warmth with diisopropyl ether. (Excess 2-bromothiophene can be recovered from the diisopropyl ether 6j.)

The solid product is dissolved in hot DMF, filtered, and the filtrate is dropped in ice water. The fancy

7

630350

Product (crude yield 59 g) is recrystallized from acetone / CH3OH or acetonitrile.

Yield 46.4 g

Yellow crystals of mp. 232-233 ° C

b) The nitro compound (4 a) is dissolved in dimethylformamide and hydrogenated with Raney nickel as a catalyst at 50 ° C. and 50 atm for 2 hours. Then it is filtered and the DMF solution is dropped into three times the amount of ice water. The precipitated amine is boiled out with CH3OH.

Analytical sample from nitromethane.

Colorless crystals with a melting point of 220-221 °

Example 5

3-A mino-4- (3-thienyl) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester, not so.

ch n - c = no-s x h 2

a) 3-Nitro-4- (3-thienyl) -5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester

70 g of methyl 3-nitro-4-chloro-5, N, N-dimethylaminomethylenaminosulfonylbenzoate are mixed with 60 g of copper powder and 100 g of 3-bromothiophene and heated to 180 ° C. under nitrogen for 4-5 hours.

Refurbishment analogous to example (4 a)

Recrystallization from glacial acetic acid or acetonitrile, mp. 197-198 ° C

b) The nitro compound is dissolved in DMF and hydrogenated for 3 hours at room temperature and normal pressure using Raney nickel as a catalyst. After filtration, the filtrate is dropped into ice water and the precipitated product is isolated. Recrystallization from CH30'H or CH3N02.

Mp 220-221 ° C

Example 6

2-amino-4,2'-di-methoxycarbonyl-6-N, N-dimethylamino-methyleneaminosulfonyl-biphenyl

10th

15

20th

ch.

a) 2-Nitro-4,2'-di-methoxycarbonyl-6-N, N-dimethyl-aminomethyleneaminosulfonyl-biphenyl

95 g (0.27 mol) of 2-nitro-4-chloro-5-N, N-dimethylamino-25 methyleneaminosulfonylbenzoic acid methyl ester are combined with 35 g of the finest copper powder (0.55 mol) and 83 g (0.31 mol) Methyl 2-iodobenzoate heated under reflux for 4 hours in absolute dimethylformamide.

The solvent is then evaporated off and the residue is digested several times with hot acetone. The acetone fractions are concentrated together and the residue is recrystallized from CH3OH / a little acetone.

53 g of the light yellow product of mp. 168-169 ° C. are obtained.

35 b) The nitro compound (6 a) is abs. DMF dissolved and hydrogenated with Raney nickel as a catalyst at room temperature and normal pressure for 4 hours. It is filtered and the product is precipitated with water.

When recrystallizing or heating in a solvent e.g. The product immediately freezes to form the 5,6-dihydro-phenanthridine system.

Claims (3)

630350 2nd PATENT CLAIMS 1. Process for the preparation of aromatically substituted sulfamoylbenzoic acid derivatives of the formula I coor- cd coor (IV) 1 a mono- or bicyclic aromatic carbo- in the cyclic or heterocyclic ring system, R1 is an alkyl group with 1 to 4 carbon atoms, R2 is hydrogen or, substituted one or more times in the various positions, halogen, alkyl or alkoxy groups with 1 to 3 carbon atoms, 3,4-methylenedioxy, Benzoyloxy, -NOa, -C = N, OH, formyl, acetyl or a carboxylic ester function -COOR, in which R represents an alkyl radical, and B the protective group R \> i / \ = c - n, x5 / wherein R3, R4 and R5 represent the same or different lower alkyl groups, R3 can also represent a hydrogen atom, and / or two of the substituents R3, R4 or R5 can also be cyclically linked to one another, characterized in that 3-nitro -4-halogeno-benzoic acid derivatives of the formula II io NR- in which the radicals R1 to Rs and © have the meaning given above, and adorn the compounds of the formula IV réduis. 2. Process for the preparation of aromatically substituted sulfamoylbenzoic acid derivatives of the formula I ' 20th 25th (D R ^ R N b'NO2S in which (Ar 1 is a mono- or bicyclic aromatic car-30 V / bocyclic or heterocyclic ring system, R1 'hydrogen, R2 hydrogen or, substituted one or more times in the various positions, halogen, alkyl or alkoxy groups with 1 to 3 carbon atoms, 3,4-methyl-35-lendioxy, benzyloxy, -N02, - Ce = N, OH, formyl, acetyl or a carboxylic ester function -COOR, in which R is an alkyl radical and B 'are two hydrogen atoms, characterized in that 3-nitro-4-halogeno-benzoic acid derivatives of the formula II 40 no. (ii) r c00r " 45, I. in which X is chlorine, bromine or iodine and R1, R3, R4 and R5 have the above meaning, with compounds of the formula III coor (ii) 1 50 R (Ar) Y (III) in which X is chlorine, bromine or iodine, R1 is an alkyl group having 1 to 4 carbon atoms and R3, R4 and Rs are the same or different lower alkyl groups, R3 can also be a hydrogen atom, and / or two 55 of the substituents R3, R4 or R5 can also be cyclically linked to one another, using compounds of the formula III where Y is halogen and R2 and ie © di R the specified 60 benen meanings, in the presence of copper powder to compounds of formula IV 0-5 (iii) 65 in which Y is halogen and R2 and ie ^ Ar ^ di have the meanings given, in the presence of copper powder to give compounds of the formula IV 3rd 630350 '' * \ SR 3 carbon atoms, 3,4-methylenedioxy, benzyloxy, -N02, -C = N, OH, formyl, acetyl or a carboxylic ester function -COOR, in which R is an alkyl radical, and B is the protective group = no in which the residues R1 to R5 and ^ Ar ^ di oor the above meaning (iv) 1 r- = c - n. 10th \ r5 / have, and the compounds of the formula IV are reduced and, before the reduction of the nitro group, the compounds of the formula IV or after the reduction of the nitro group, the compounds of the formula I. coor 1 wherein R3, R4 and R5 represent the same or different lower alkyl groups, R3 can also represent a hydrogen atom, 15 and / or two of the substituents R3, R4 or R5 can also be cyclically linked to one another, which is characterized in that 3-nitro-4-halogeno-benzoic acid derivatives of the formula II 20th (I) where R1, R2 and © have the meanings given above and B the protective group 25th '-V v ■ VRP = no coor (ii) 1 30 in which X is chlorine, bromine or iodine and R1, R3, R4 and R5 have the above meaning, with compounds of the formula III r3 ^ \ c - n. , ni5 ' wherein R3, R4 and R5 represent the same or different lower alkyl groups, R3 can also represent a hydrogen atom, and / or two of the substituents R3, R4 or R5 can also be cyclically linked to one another, means hydrolyzed with acid or alkali.