DK142110B - Process for the preparation of carboxylic acid amides. - Google Patents

Description

142110

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a novel process for the preparation of carboxylic acid amides of the general formula I set forth in the preamble of the claim, and the process is characterized by the characterizing portion of the claim. eg. Danish presentation no. 129.44,

Furthermore, the preparation of compounds, which are closely related, is known from e.g. Danish forward publication no. 130,679 and Danish patent no.

124,256.

One of the known methods relates to reactions between a carboxylic acid compound and an amino compound present in the form of a hydroxyamino compound. In order for the reaction between these two compounds to proceed, heating must be heated to excessively high temperatures to induce a dehydration, because a heating at constant temperatures gives nothing but the formation of the salt of the carboxylic acid. However, this known method 20 is not applicable to most of the complicated compounds disclosed in the process of the present invention as these compounds decompose at high temperatures.

Therefore, it is common practice to cause the two compounds to react with one another after converting one of them into its reactive derivative in order to form the amide bond.

(RCHO 0Xlderil * 6 -ή RC00H- * RCOA + EySR'-5> RCONHR'-4 RCOHHR '' (R'NHOH red, uctfon *) R'HH -> RC00H + DNHR '- ^ RCOHHR' -RCOSfHR '' 2 2

OR

Wherein A is e.g. halogen, -OC00R1, or '° ® ^' is "" "\ q 3 'where R1, R2 and R3 are e.g. is alkyl, phenyl or the like.

However, to produce RCOA, complicated operations such as formation of a chloride by treatment with e.g. thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride (and further formation of an azide by treatment of the formed chloride with sodium azide), or preparation of an acid anhydride by treatment with e.g. ethyl chloroformate in the presence of a base. Furthermore, these compounds are extremely harmful or present a risk of explosion. Therefore, in order to use these compounds, it is necessary to have equipment to prevent dangerous effects and explosions, which requires enormous expense in the preparation of the reaction plant. Furthermore, as the waste products resulting from these reactions are hazardous, the planning of such a plant will present very serious problems with regard to placement, especially in the vicinity of inhabited areas in developed areas, where industrial scale production will be virtually impossible. Also in the case where there is an activation of amines, e.g. when ^ OR or equal to 3 X0R; 5 nepde is used, various problems such as those stated above occur.

By contrast, if an aldehyde compound and a hydroxy compound are used as starting materials, a complicated activation is not necessary and the formation of an amide bond to produce the desired compounds proceeds, as shown in the following reaction scheme: XCHO + HOKHR * - ? XCH = N - R '-> XCH = ER *' -> XCONHR '' 4 '4/0 0

IIa lab la 25 where an aldehyde compound is reacted with a hydroxyamine compound to give an E-substituted aldaxime compound of the general formula IIa (hereinafter called the nitron compound), followed by reaction, if necessary, by converting the substituent R -30 viscous substituent R1 '. Then, the resulting nitron compound IIa or IIb is subjected to a heating according to the invention to obtain the desired compound of the general formula Ia which is identical to compound I, provided that R 'and / or R'1 represent -I SO ^ EHR, where 35 Ϊ and R are as defined in the claim.

3 142110

The nitron formation (the preparation of the N-substituted aldoxime of the general formula II) is readily obtained by simple heating in an alcohol in the presence of sodium ethoxide. The yield of the nitron compound prepared after this reaction is high.

Also, the actual preparation of the desired product I is obtained with great yield by simple heating in acetic anhydride and acetic acid for a short time to a temperature between + 0 ° C and the boiling point of the reaction mixture.

10 The carboxylic acid amides I and their salts have a potent and long-lasting effect against hypoglycemia and are useful as useful agents in this regard, see e.g. Arzneim. Forsch.

16, 16U0 (1966) and the aforesaid disclosure no.

I 29 - 4 · 1 U.

The N-substituted aldoxymers (nitrons) II used as starting compounds in the present process are novel compounds which can be prepared by various processes, some of the typical methods being the following: Process A (Examples 1 and 2)

II

X-CH = NOH + AY- | ~ -j- · SO2NH2 (ΤΛ -> X-CH = NYH- 4 ~ SO_NH0 in Ks? Where A is an atom or group which can react with a hydroxyimino group to form a nitrone structure, such as a halogen atom, a sulfonic acid residue or / quaternary ammonium salt residue, and X and Y have the above meaning.

The reaction may be carried out in the presence of an acid eliminant such as an organic or inorganic base, e.g. sodium ethoxide, sodium hydride, pyridine or basic ion exchange resin, usually in a solvent, e.g. methanol, ethanol, acetone, benzene or dimethylformamide, at a temperature of from 0 ° C to the boiling point of the solvent.

142110 2) u

X-CH = H-Y-1-4 S G HH + B'NCO

Ί '\ sy d ά J ^ s ___ ^ X-CH = ET-Y-J- -L_ SOgNHCOUHR' o where X, Y and R * have the above meanings.

The reaction may be carried out by a conventional method per se using an isocyanate. Process B (Examples 3 and 12) aCH = M4 \ SO raCOMR '

k l J

__________ HONH-Y - j - SOgNHCONHR '5 where Y and R' each have the aforementioned meanings.

The reaction may be carried out in the presence of an acid or a base in an aqueous medium.

2) r "V

X-CHO + HOHH-Y — JJ- -4— SO HHCOHHR '—---- ϊ X-CH = H-Y— | - -j— SOgHHCONHR' where X, Y and R 'each have the above meanings.

The reaction may be carried out in the usual manner in a solvent, e.g. water, methanol, ethanol, benzene, toluene or dimethylformamide, at a temperature of from 15 ° C to the boiling point of the solvent.

Process C (Examples 5, 8, 9 and 10) X-CHO + HOHH-Y-J | - -J-SO ^ HHg ___ x X-CH = HY-II- -I-SOONH_ '^ where X and Y each has the above meanings.

The reaction can be carried out in substantially the same manner as method B (2).

2) ^ X-CH = N-Y-J (--- SO2NH2 + R'NC0 _> X-CH = N-Y-U-SO2NHC0NHR * 0 where X, Y and R 'each have the above meanings.

The reaction may be carried out in substantially the same manner as in Process A (2).

Method D (Examples 6 and 7) 1)

X-CH = J-Y - [} - ^ Jj-SO2 NH2 + ClCOOB

- * X-CH = | "Y ~ ^^ ~ SOgNHCOOB

where B is a lower alkyl group or a phenyl group and X and Y each have the above meanings.

The reaction can be carried out, usually in the presence of an acid-eliminating agent, in a manner known per se.

2> X-CH = N-Y-U- -j— S02NHC00B + R'NHg ^^ /% _ ^ X-CH = N-Y— | ^ j-j-S02NHC0NHR 'where X, Y, R' and B each have the above meanings.

The reaction can be carried out in a conventional manner for aminolysis of carbamic acid esters.

Practical and preferred embodiments of the invention are described in more detail in the following Examples, however Examples 1-10 deal with the preparation of some starting compounds and Example 12 deals with the preparation of N- [p- (β-hydroxyaminoethyl) -benzenesulfonyl] -N ' -cyclohexyl urea useful for the preparation of the nitrons specified in claim 6 of 142110 of general formula IX wherein R = COM. CgH ^ 1. '

Example 1.

2.9 g, 0.027 mol, anti-benzaldoxime are dissolved in 50 ml of absolute ethanol containing 1.9 g, 0.027 mol, sodium ethoxide with stirring. To the resulting solution is added 5.3 g, 0.02 mole, p- (ω-bromethyl) -benzenesulfonamide and the resulting mixture is stirred for about 7 hours until slightly alkaline. The ethanol is distilled off under reduced pressure and the remaining 10 residue is added to 50 ml of ice water. The mixture is made slightly acidic or neutral with dilute hydrochloric acid. The precipitated precipitate is filtered off, washed with water and dried to give 5.1 g of α-phenyl-E-α- (p-sulfamoylphenyl) ethyl J-nitron as white crystals. Yield 8 ^, 0%. Melting point 205-208 ° C.

Example 2.

9.0 g, 0.03 mole, od-phenyl-M- [O - (p-sulfamoylphenyl) ethyl] nitrone is added to 150 ml of absolute acetone, to which is added 10.3 g, 0.075 mole, anhydrous potassium carbonate. The reconstituting mixture is heated at reflux and with stirring for 2.5 hours. After the addition of 5.6 g, 0.05 mol, cyclohexyl isocyanate, the resulting mixture is refluxed for 7 hours. The acetone is distilled off under reduced pressure. The remaining white residue is added to ice water, 2.5 and the undissolved material is separated by filtration. The filtrate is made slightly acidic or neutral with dilute hydrochloric acid to give 1, 6 g of o-phenyl-N- [O- (p-cyclohexylcarbamoylsulf a-moylphenyl) ethyl] -nitron. Yield 93%. Melting point 92-96 ° C.

Example 3 17.2 g, 0.1 mole, 5-chloro-2-methoxybenzaldehyde and 37.9 g, 0.1 mole, U-Lβ- (β-hydroxyaminoethyl) -benzenesulfonyl] -N'-cyclohexylurea hydrochloride are added. to 700 ml of absolute ethanol and the resulting mixture is stirred at room temperature for 3 hours. The ethanol is then distilled off under reduced pressure. After cooling, the precipitated crystals are separated by filtration, washed with absolute ethanol and dried, yielding 1 + 6.1 + g of α- (5-chloro-2-methoxyphenyl) -N- [O- (p hexylcarbamoylsulfamoylphenyl) ethyl] -nitron as white crystals. Yield 95.5% · Melting point 90.8-96.0 ° C.

Example 1+.

5 3L +, 3 g, 0.2 mol, 5 ~ chloro-2-methoxybenzaldehyde and.

Dissolve 65.5 g, 0.2 mol, p- (ω-hydroxyaminoethyl) -benzenesulfonamide hydrochloride in 700 ml of absolute ethanol, and the resulting mixture is stirred at room temperature for 5 hours. The ethanol is evaporated from the reaction mixture under reduced pressure 10 to give about 180 ml. After cooling, the precipitated crystals are separated by filtration, washed with ethanol and dried to give 61 +, 6 g of α- (5-chloro-2-methoxyphenyl) -N- [O- (p-sulfamoylphenyl) ethyl] -nitron. Yield 85.0%. Melting point 221 +, 0-225.5 ° C.

Example 5 · 36.8 g, 0.1 mole, α- (5-chloro-2-methoxyphenyl) -N- [O- (p-sulfamoylphenyl) ethyl] nitrone is added to 500 ml of absolute acetone and added thereto an additional 31 g of anhydrous potassium carbonate. The resulting mixture is heated under reflux and with stirring for 2.5 hours. After addition of 15.0 g, 0.12 mol, cyclohexyl isocyanate, the resulting mixture is heated at reflux and under vigorous stirring for 7 hours. The acetone is distilled off under reduced pressure.

To the remaining white residue, ice water is added and the 25 undissolved material is separated by filtration. The filtrate is made slightly acidic with dilute hydrochloric acid. The precipitated precipitate is separated by filtration, washed with water and dried to give 1 + 3.1 g of α- (5-chloro-2-methoxy-phenyl) -N- [O- (p-cyo-10-hexylcarbamoylsulfamoylphenyl) ethyl] nitrone. Yield 30 91.0%. Melting point 92.6-96.8 ° C.

Example 6

30.1+ g}, 1 mol, α-phenyl-N- [O- (p-sulfamoylphenyl) ethyl] nitrone is added to 500 ml of absolute methyl ethyl ketone and additionally, 27.6 g, 0.2 mole, anhydrous are added potassium carbonate. The resulting mixture is heated at reflux and with stirring for 1 hour. After cooling, 28.1+ g, 0.3 mole, methyl chloroformate is added to the mixture, which is gradually heated under reflux for 5 hours. The precipitate is separated, separated by filtration, washed with methyl ethyl ketone and dissolved in water. The resulting solution is filtered and slightly acidified with dilute hydrochloric acid. The precipitated precipitate is filtered off, washed with water and dried to give 29.3 g of cr-phenyl-N-t t-Cβ-methoxycarbonylsulfamoyl-phenyl) -ethyl] -nitrone. Yield 81.0%.

Example 7

Dissolve 36.2 g, 0.1 mole of α-phenyl-U- [O- (p-methoxycarbonylsulfamoylphenyl) ethyl] nitrone in 700 ml of absolute methanol and add to this solution 12 g of O 11 moles, cyclohexylamine. The resulting mixture is heated under reduced pressure to evaporate the methanol. The residual residue is heated to 115 to 120 ° C for 1 hour. After cooling, the precipitated solid white material is crushed, washed with a small amount of methanol and dried under reduced pressure to give 32.7 g a white powder. Yield 78.0%. Melting point 92-96 ° C.

Example 8.

29.5 g, 0.1 mole, α- (5-methylisoxazol-3-yl) -N- [1- (p -sulfamoylphenyl) ethyl] -nitrone are added to 500 ml of absolute acetone and added to this an additional 31.0 g , 0.22 mol, anhydrous potassium carbonate. The resulting mixture is heated at reflux and with stirring for 3 hours. After addition of 13.3 g, 0.12 mol, cyclopentyl isocyanate, the mixture is heated at reflux and with stirring for 6 hours. The acetone is evaporated under reduced pressure. The residue is dissolved in water and the undissolved material is filtered off. The filtrate is made slightly acidic with dilute hydrochloric acid.

The colorless precipitate is separated by filtration, washed with water and dried under reduced pressure to give 28.1 g of α- (5-methylisoxazal-3-yl) -N- [O- (p-cyclopentylcarbamoylsul-famoylphenyl) ethyl ] -nitron, as a colorless powder. Yield 83.0%.

Example 9 · 12.6 g, 0.05 mol, p- (β-hydroxyaminoethyl) -benzenesulfonamide hydrochloride is dissolved in 500 ml of absolute ethanol, and to this solution is then added 9.6 g »0.055 mol, 3, k-dichlorobenzaldehyde. The resulting mixture is stirred at room temperature for 8 hours and then concentrated by evaporation of the ethanol. After cooling, the precipitated 5 crystals are separated by filtration, washed with a small amount of cold methanol and dried under reduced pressure to give 1.6 g of α- (3,1-dichlorophenyl) -N- [£ 3- (p- sulfamoylphenyl) ethyl] -nitron. Yield 78%. Melting point 210-212 ° C.

Example 10, 5 g, 0.013 mole, α- (3,1-dichlorophenyl) -N- [8- (p-sulfa moylphenyl) ethyl] -nitrone is dissolved in 250 ml of absolute acetone and to this solution is added another 5 g anhydrous potassium carbonate. The resulting mixture is heated at reflux for 2 hours. After addition of 3 g, Q, 02k mole, cyclohexyl isocyanate, the resulting mixture is refluxed for 6 hours. The acetone is distilled off under reduced pressure. The residue is dissolved in water and the undissolved material is separated by filtration. The filtrate is made slightly acidic with dilute hydrochloric acid. The precipitated precipitate is separated by filtration, washed with water and dried under reduced pressure to give 8 g of α- (3 .

Yield% · Melting point 90 ~ 92 ° C.

Example 11.

25 l *, 2 g, 0.01 mol, α-phenyl-N- [8- (p-eyclohexylcarbamoylsulfamoylphenyl) ethyl] nitrone are added to 15 ml of a 1: 1 mixture of glacial acetic acid and acetic anhydride, and the resulting mixture is heated to 90-95 ° C with stirring for a few minutes. After cooling, the reaction mixture is immediately poured into 150 ml of ice water. The separated crystals are separated by filtration, washed with water and dried. Recrystallization in methanol gives 3.7 g of N- [p- (8-benzaminoethyl) -benzenesulfonyl] -N1-cyclohexylurea. Yield 87% · Melting point 189-190 ° C.

Similarly, the following compounds are prepared: 35 N- [p- (β-2-thienylcarbonylaminoethyl) -benzenesulfonyl] -N'-cyclohexylurea, yield 75%, mp 191-193 ° C; N-1β- (8-2-furoylaminoethyl) -benzenesulfonyl] -N'-in-butbutylurea, yield 82%, m.p. 189-192 ° C.

10 142110

Example 12.

k2.9 g, 0.1 ml, α'-phenyl-U ~ [3- (p-cyclohexylcarbamoylsulfamoylphenyl) ethyl J-nitron is added to 100-ml of a 1: 1 aqueous hydrochloric acid and the resulting mixture is heated 5 on water bath with stirring for 25 min. The resulting benzaldehyde is distilled off from the reaction mixture by steam distillation, then water and hydrochloric acid are distilled off under reduced pressure to give 33.8 g of U- [p- (β-hydroxyamino-ethyl) -benzenesulfonyl] -jr r-cyclohexylurea hydrochloride 10 like white crystals. Yield 89.0%.

Example 13 * 9.5 g, 0.02 mole, o- (5-ehloro-2-methoxyphenyl) -N- [β- (p-cyclohexylcarbamoylsulfamoylphenyl) ethyl] nitrone is added to 30 ml of a 1; 1 mixture of glacial acetic acid and vinegar-13 acid anhydride, and the resulting mixture is heated to 70 ° C with stirring for 8 min. After cooling, the resulting mixture is added to 300 ml of ice water with stirring. The separated crystals are separated by filtration, washed with water and dried. Recrystallization in methanol gives 8, tg 20 υ- [ρ- · {β- (5-'Chloro-2-methOxybenzamino Jethylj -b a zen sulfonyl Ι Ε '-eyclohexylurea as white crystals. -170 ° C.

Example 1k 36.9 g, 0.1 mol, α- (5-chloro-2-methoxyphenyl) -H- [3-25 (p-sulfamoylphenyl) ethyl] nitrone is added to 80 ml of a 1: 1 mixture of glacial acetic acid and acetic anhydride, and the resulting mixture is heated to 90-95 ° C with stirring for 5 minutes. After cooling, the reaction mixture is immediately poured into ice water. The precipitated crystals are separated by filtration, washed with water, dried under reduced pressure and recrystallized in methanol to give 33.5 g of p- [β ~ (5-chloro-2-methoxy-benzaraine) ethyl] -benzenesulfonaride as a white crystalline powder. Yield 91.0%. Melting point 213-216 ° C.

Example 15

39.9 g, 0.1 mol, c * - (5-methylisoxazol-3-yl) -N- [β- (β-

cyclopentylcarbamoylsulfamoylphenyl) ethyl] nitrone is added to 120 ml of a 1: 1 mixture of glacial acetic acid and acetic anhydride and the resulting mixture is heated to 70-75 ° C

142110 1 1 with stirring for some min. The reaction mixture is cooled and added to 1000 ml of ice water to decompose acetic anhydride. After stirring for some time, the precipitated precipitate is separated by filtration, washed with water and dried under reduced pressure to give 3, 6 g of N- [p- [$ - (5-methylisoxazol-3-yl-carbonylamino) ethyl] benzenesulfonyl] -N'-cyclopentylurine as a colorless crystalline powder. Yield 89.0%. Melting point 207_209 ° C.

Similarly, the following compounds are prepared: 10 N- [p- (3-methylisoxazol-5-yl-carbonylaminoethyl) -berisulphonyl] -N'-cyclohexylurea, m.p. 193-195 ° C; N-lp-β-β- (1,5-dimethylpyrazol-3-yl-carbonylamino) -ethyl-benzenesulfonyl] -N'-cyclohexylurea, m.p. 20U-207 ° C.

Example 16.

In the same manner as that described in Example 11, α- (3,3-dichlorophenyl) -N- [8- (p-cyclohexylcarbamoylsulfamoylphenyl) ethyl] nitrone is converted to Ν- [ρ £ β ~ ( 3, ^ - dichloro benzene-amino) -ethyl} -benzenesulfonyl] -Ν'-cyclohexylurea. Melting point 186-189 ° C.