DE2658300A1 - 3,5-BIS- (ACYLAMINO) -BENZAMIDE - Google Patents

Description

KRAUS & WEISERT 2653300

FATE NATIONAL LAWYERS

DR. WALTER KRAUS DIPLOMA CHEMIST DR.-ING. ANNEKÄTE WElSERT DIPL.-ING. SPECIALIZATION CHEMISTRY IRMGARDSTRASSE 15 D-8OOO MÜNCHEN 71 -TELEPHONE O89 / 797O77-797O7B TELEX 05-212156 kpat d

TELEGRAM KRAUS PATENT

PG-OO54 1414 WK / MY

MALLINCKRODT, INC, St. Louis / USA

3,5-bis (acylamino) benzamides

The invention relates to new 3,5-bis- (low-acylamino) -benzamides, Process for their preparation and the use of such compounds.

Certain 3,5-disubstituted-2,4,6-triiodanilides of monobasic Polyhydroxycarboxylic acids have proven themselves in recent years. Time proved to be a suitable non-ionic X-ray contrast medium. Examples of such compounds are 3-gluconamido-5- [N- (2-hydroxyethyl) acetamido] -2,4,6-trijoa-N-methylbenzamide (TJS-PA 617 081 of September 29, 1975) and 3-gluconamido-N- (2-hydroxyethyl) -2,4,6-triood-5- (N-methylacetamido) -benzamide (DT-OS.2 456 685).

In the production of such coded, non-ionic X-ray contrast media are 3- (low-acylamino) -5-amino-2,4,6-triiodobenzamides important intermediates. Such intermediates have hitherto been made from commercially available 3,5-dinitrobenzoic acid produced by a series of reactions

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for which the following six-step sequence is an example:

3,5-Dinitrobenzoic acid (I) 3-Araino-5-

nitrobenzoic acid (II) ^ 3-acetamido-5-

nitrobenzoic acid (III) ■ 3-acetamido

5-aminobenzoic acid (IV) 3-acetamido

5-amino-2,4,6-triiodobenzoic acid (V) ■

3-acetamido-5-thionylamino-2,4,6-triiodobenzoyl chloride (VI) 3-acetamido-5-amino-2,4,6-

triood-N-methylbenzamide (VII)

It can be seen that this reaction is quite complex. The yields are poor and substantial Cleaning measures required. The cost of technically running this reaction would therefore be quite high.

Recently, C.L.Hakansson (GB-PS 1 374 338) a two-step process for the preparation of the compound IV from the compound I is described. This procedure goes like this follows from:

■} 3,5-diaminobenzoic acid (VIII) ^ IV.

In this method, compound VIII is dissolved in an aqueous mineral acid solution and acetic anhydride is used (Molar ratio 1 to 1.7 with respect to VIII) added in the cold. As a result, compound IV falls into shape its mineral acid salt, from which the free acid is released by treating the salt with a base *

In DT-OS 2 424 197 a further, improved process, which takes place in two stages, for the production of the Compound V described from compound VIII. This procedure works as follows:

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VIII) 3,5-bis-acetamidobenzoic acid (IX) } V.

In this process, a hot, aqueous suspension of compound VIII is treated with acetic anhydride (molar ratio 2.5 based on VIII) to form compound IX which precipitates when the solution cools. The reaction mixture is then acidified, _{treated with NaICl 2} solution and heated. Compound V precipitates after cooling.

While this is an improvement to the preparation of compound V, it is still necessary Steps to go from compound V to compound VII are complex and give poor yields and a low quality product.

The invention relates to new 3,5-disubstituted benzamides, which are suitable as intermediates for the preparation of 3- (low-acylamino) -5-amino-2,4,6-triiodobenzamides are. The invention also relates to methods of making and using these intermediates.

According to the invention, the yields are increased considerably and the number of reaction stages is reduced. Farther the cleaning measures are greatly simplified. Therefore, the total cost of this reaction is such that that for the technical implementation appears attractive. Furthermore, it is to be regarded as unexpected that a 3 »5-bis-acylaminobenzoic acid amide can be iodized. So far it has been assumed that there is a free amino group in the benzoic acid amide is required to bring about the iodination.

As used herein, the term "lower" (e.g. lower-alkyl, lower-acyl) means that the subject Group contains 1 to 6 carbon atoms. The designation

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"lower acyl" also includes lower alkanoyl, i. Acetyl, propionyl etc., and lower-alkoxy- (lower-alkanoyl), i.e. methoxyacetyl, ethoxyacetyl, methoxypropionyl etc.

The invention relates to benzamides of the general formula

CON

R ³ NH

in the

R and R for hydrogen and / or lower-alkyl groups stand and

R and R represent lower acyl groups.

These groups can be the same or different.

The 3> 5-bis (low-acylamino) -benzamides, which according to of the invention are iodized are made in the manner ^ that a 3,5-dinitrobenzamide is first hydrogenated to form the 3 »5-diaminobenzamide, which is then acylated, to form the 3 »5-bis (acylamino) benzamide.

In particular, a 3 »5-diaminobenzamide is the general formula

H ₂ N ^^ "NH ₂

in the

R and R for hydrogen and / or lower-alkyl groups stand,

prepared in such a way that a compound of the general formula

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O ₂ N

1 2

in which R and R have the meanings given above, hydrogenated to the corresponding 3,5-diaminobenzamide.

Then there is an acylated 3,5-diaminobenzamide of the general formula

CON ^ ο

3 JAL ₄ R ⁵ NH ^ v ^ MHET "

in the

R and R for hydrogen and / or lower-alkyl groups stand and

R- 'and R represent acyl groups,

produced by a 3 »5-diaminobenzamide of the general formula

H ₂ N

in the

R and R for hydrogen and / or lower-alkyl groups stand,

reacted with an acylating agent to form the acylated 3 »5-diaminobenzamide to build.

As used herein, the term "acylating agent" is intended to mean a substance which is capable of doing so is to react with an aromatic amino group in order to

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an alkanoylamino group (e.g. an acetamido or propionamido group etc.) or an alkoxyalkanoylamino group (e.g. a methoxyacetamido, thoxyacetamido or 3-methoxypropionamido group etc.). Such agents are, for example, acid anhydrides (e.g. acetic anhydride, propionic anhydride etc.) and acyl halides (such as acetyl chloride, propionyl bromide, methoxyacetyl chloride etc.).

According to the invention there are 3- (lower acylamino) -5-amino-2,4,6-trioodbenzamides the general formula

1 V

in the

XX L

H ₂ N ^ T ^ NHR

R ¹ and R ² for hydrogen and / or lower-alkyl

groups stand and

R is a lower acyl group,

prepared in such a way that one has a lower acylaminobenzamide the general formula

CONv 5
ι N _R «£

R ³ NH ^ \ ^ NHR ⁴

in the
and

12 U- R, R and R have the meanings given above

■ z

He: stands for a low acyl group,

with an iodizing agent in an aqueous medium, advantageously under acidic conditions, to form the 3- (lower acylamino) -5-amino-2,4,6-tri3odbenzamide.

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Iodizing agents suitable for this purpose are e.g. solutions of iodine, iodine monochloride, HJClp » Sodium iodine dichloride and potassium iodine dichloride.

According to a further embodiment of the invention, a process for the preparation of 3- (lower-acylamino) -5-amino-2,4,6-triiodobenzamides was found considered, which is characterized in that one is a 3,5-dinitrobenzamide hydrogenated to a 3,5-diaminobenzamide, the 3 »5-diaminobenzamide reacted with an acylating agent to form an acylated 3,5-diaminobenzamide, and that the acylated 3,5-diaminobenzamide with an iodizing agent in an aqueous medium, advantageously under acidic conditions, to the 3- ^ iiedrig-acylamino) -5-amino-2,4,6-trioodbenzamide form.

Examples of compounds considered according to the invention are the following substances:

3,5-bis-acetamido-N, N-dimethylbenzamide, 3,5-bis (methoxyacetamido) -N-methylbenzamide, 3,5-bis-acetamido-N- (propyl) -benzamide, 3,5-bis-acetamido-N, N-diethylbenzamide.

Hydrogenation of the 3,5-dinitrobenzamide is preferred carried out in a solution of the dinitrobenzamide in a solvent for this purpose Hydrogen is reduced, e.g. in a lower alkanol (such as methanol, ethanol etc.), a lower aliphatic Ester (such as ethyl acetate) or a lower aromatic hydrocarbon (such as toluene). It can also be in a slurry of the dinitrobenzamide in water and hydrochloric acid are effected, with a progression of the reduction Amine hydrochloride is formed and dissolution is effected. The hydrogenation of the dinitrobenzamide is preferably carried out with hydrogen at elevated pressure in the presence of a hydrogenation

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catalyst, for example Raney nickel, or preferably a noble metal catalyst deposited on a support, -zB of 5% platinum or palladium-on-carbon, carried out. Actual pressure is not critical and hydrogen pressures in the range of about 0.70 to 3.52 atmospheres (10 to 50 psig), for example, are suitable.

After the theoretical amount of hydrogen has been absorbed the catalyst is filtered off and the 3,5-diaminobenzamide can be isolated, for example, by evaporating the solvent will.

Alternatively, the nitro groups can be removed by means of a reducing / hydrogenating agent such as iron and hydrochloric acid or tin and hydrochloric acid can be reduced to amino groups.

Preferably the diamine is converted into the dihydrochloride or another acid addition salt. This can be done, for example, by drying Introducing hydrogen chloride into the solution of the diamine in order to precipitate the dihydrochloride, or that the solution of the diamine mixed with an excess of aqueous hydrochloric acid solution and the resulting solution evaporated to dryness.

The acylation of the 3 »5-diaminobenzamide takes place on best in such a way that you first prepare an aqueous solution of the diamino compound in the form of a salt. if the diamino compound is isolated as a salt (e.g. as a dihydrochloride) after the hydrogenation reaction, then the salt simply be dissolved in water. On the other hand, if the diamino compound is isolated as the free amine, then it can be dissolved in water which contains sufficient acid, suitably hydrochloric acid or another common mineral acid, to cause the amine to dissolve. The acylation is preferably carried out at reduced temperature,

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- Ϊ7 ""

Λ *

to minimize hydrolysis of the acylating agent by water. The temperature should preferably be below about 30 ° C. The acylating agent is preferably used in added small portions to the cooled solution of the diamine. Alternatively, the diamine can also be in a suitable organic Solvent, e.g., ethyl acetate, toluene, etc., can be dissolved and the acylating agent can be added to this solution are given. In certain cases the acylating agent itself (e.g. acetic anhydride) can be used as the solvent / reaction medium serve for the diamine.

The degree of acylation of the diamine depends on the relative amount of acylating agent added. Usually exists when the mole ratio of acylating agent to diaminobenzamide is in the range from about 1 to about 1.5 the product is mainly composed of the monoacylamino derivative. As the level of acylating agent increases, it decreases the proportion of the bis-acylamino derivative in the product also increases. The use of from about 2 to about 4 moles of acylating agent / mole Diaminobenzamide provides a product which, with varying lesser amounts of the monoacylamino derivative, mainly consists of the bis-acylamino derivative.

As stated above, the invention also relates to the iodination of an acylated 3 »5-bis ~ (lower acylamino) benzamide to a 3- (lower acylamino) -5-amino-2,4,6-triiodobenzamide. The iodination is followed by the deacylation an acylamino group to form the desired 3- (lower acylamino) -5-amino-2,4,6-triiodobenzamide accompanies .. It takes place in the usual way, with a sufficient amount of the iodizing agent is used to effect triiodination. Preferably it is submerged in an aqueous medium acidic conditions, i.e. at an acidic pH below 1 to about 6, at the iodination temperature, i.e. 20 to 85 ° C. For example, if sodium iodine dichloride

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(NaJCl ₂ ) is used, then about 3 equivalents thereof are used per equivalent of the 3,5-bis (lower acylamino) benzamide. It is generally added as a 2.4N solution over a period of 1 to 30 minutes to the acylaminobenzamide in an aqueous medium. The mixture is stirred for 2 to 15 hours, and the iodination is completed by 4- to 1Ostündiges heating at 65 to 85 ⁰ C.

According to the nomenclature rules of a benzamide, every position of the ring that is meta-related to the carboxamide group can be ^{numbered "3", in which case the other meta-position is given the number n 5 "} Invert numbering more or less arbitrarily in order to satisfy special nomenclature purposes.

The invention is illustrated in the examples.

example 1

3,5-diamino-N-methylbenzamide dihydrochloride

3,5-Dinitro-N-methylbenzamide (GB-PS 866 516 - 0.1 mole, 22.5 g) was slurried in methanol and the slurry and reaction vessel purged with nitrogen. Catalyst (5% Pd / C, 3.0 g) was added and the nitro groups were reduced with hydrogen at elevated pressures (0.70 to 3 »52 atmospheres). The theoretical amount of hydrogen (0.6 mol) to form 3,5-diamino-N-methylbenzamide was taken up in the reaction. The catalyst was filtered off and the filtrate was allowed to run into a solution of hydrochloric acid (20 ml of water + 20 ml of concentrated acid, 0.2 mol of HCl). The resulting solution was evaporated to dryness under reduced pressure, leaving a residue of 3,5-diamino-N-methylbenzamide dihydrochloride.

70982 771088

Example 2

Production of 3-acetamido-5-amino-N-methylbenzamide hydrochloride from 3> 5-diamino-N-methylbenzamide

The residue of the 3,5-diamino-N-methylbenzamide dihydrochloride (0.1 mol) from Example 1 was dissolved in water (75 ml) and the solution was cooled to 12 ° C. Acetic anhydride (0.15 mole, 15.3 g) was added dropwise over 30 minutes in while the temperature was maintained at 12 to 15 ⁰ C. After about 2/3 of the acetic anhydride had been added, 3-acetamido-5-amino-N-methylbenzylide hydrochloride began to precipitate. The agitation was increased and the remainder of the acetic anhydride was added. The suspension was stirred for a further 30 min at 12 to 15 ^{° C. and filtered.} The solids were air dried for 24 hours to give 21.2 g of product (87.0%). Analysis by thin layer chromatography (25: 5: 1, chloroform: methanol: ammonia) indicated that the crude product contained about 1 to 3% 3,5-diainino-N-methylbenzamide and about 10 to 20% 3,5-diacetamido -N-methylbenzamide in addition to the desired 3-acetamido-5-amino-N-methylbenzamide hydrochloride.

Example 3
3-acetamido-5-amino-2,4,6-triiodo-N-methylbenzamide

The crude 5-acetainido-3-amino-N-methylbenzane & d-hydrochloride of Example 2 (0.05 mol, 12.2 g) was dissolved in water (150 ml) and a 2.42N solution of NaICl ₂ (68 ml, 0.165 mol) was added over 15 minutes. The reaction mixture was heated and stirred at 75 ° C. for 15 to 20 hours. The reaction mixture was ^{cooled to 30 °} C. and filtered. The solids were reslurried in water (100 ml) and filtered. The solids were then reslurried in methanol (50 ml) and filtered. After air drying overnight, it became a dark yellow material

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(14.5 g, 49.6% yield). The NMR and IR spectra as well as thin-layer chromatographic analysis (25: 5: 1, C3iloroform: methanol: ammonia) indicated that the The product is essentially pure 3-acetamido-5-amino-2,4,6-triiodo-N-methylbenzamide depicted. The thin layer chromatographic results indicated the presence of a very small amount of an impurity with a lower R ^ Value, which is presumably a diode connection acted.

Example 4

3,5-bis-acetamido-N-methylbenzamide

3 »5-diamino-N-methylbenzamide dihydrochloride (0.1 mol), prepared according to example 1, was in water (750 ml) of 25 ° C dissolved. Acetic anhydride (0.25 mole, 25 g) was added over 20 minutes. The solution was another 45 min stirred and additional acetic anhydride (0.05 mol, 5 g) was added. Stirring was continued for 45 minutes, after which time another aliquot of acetic anhydride (0.05 mol, 5 g) was added. Finally, stirring was continued for a further 30 minutes. The thin-layer chromatographic analysis (25: 5: 1, chloroform: methanol: ammonia) of the reaction mixture showed point out that the crude product mainly consisted of the 3> 5-bis ~ acetamido-N-methylbenzamide and about 5 to 10% 3-acetamido-5-amino-N-methylbenzamide.

Example 5

Preparation of 3-acetamido-5-amino-2,4,6-triiodo-N-methylbenzamide from 3,5-bis-acetamido-N-methylbenzamide

The reaction mixture of Example 4 was diluted with water (250 ml) and heated to 45 to 50 ⁰ C. A solution of 2.4N NaICl ₂ (0.33 mol, 138 ml) was added over 30 minutes. The reaction mixture was ^{cooled to 25 °} C. and stirred overnight. The slurry was heated to 70 to 72 ° C

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heated and stirred for 6.5 h. Then it was cooled to 3O ⁰ C and filtered. The solids were first reslurried in water (200 ml) for 4 hours and then refluxed twice in methanol (150 ml) for 4 hours. The light, dark yellow solid was air dried overnight to give 41.0 g (70.1%) of product. The NMR and IR spectra and analysis by thin layer chromatography (25: 5: 1, chloroform: methanol: ammonia) indicated that the product was predominantly 3-acetamido-5-amino-2,4,6-triiodo-N -methylbenzamide was. The results of thin layer chromatography indicated the presence of a small amount (estimated to be < 2% ) of a material with a lower R ^ value, which was believed to be a diiodine compound, and a small amount (estimated to be < 2% ) of one Material with a higher R ~ value, which was presumably 3 »5-diamino-2,4,6-triiodo-N-methy! Benzamide.

Other compounds according to the invention than specifically described above can be followed by similar Methods are made. For example, the treatment of a solution of a 3,5-diamonobenzamide, e.g. of 3,5-diamino-N-methylbenzamide, with a lower alkoxy (lower acyl) halide, e.g., methoxyacetyl chloride, at generally similar Conditions as described above for the formation of a mixture of acylated products, depending on the one used Proportions of 3j5-diaminobenzamide and acylating agent varying proportions of 3-amino-5- (lower alkoxy-lower acylamino) benzamide (e.g. 3-amino-5-methoxyacetamido-N-methylbenzamide) and of 3,5-bis- (lower-alkoxy-lower acylamino) -benzamide (e.g. 3,5-bis- (methoxyacetamido) -N-methylbenzamide) contain. The diacylated product can then be iodinated under the conditions generally described above, the corresponding 3-amino-5- (lower-alkoxy-lower acylamino) -2,4,6-triiodobenzamide (e.g. 3-amino-5-methoxyacetamido-2,4,6-triiodo-N-methylbenzainide) is formed.

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Claims (12)

2658 2 00 Claims 1. 3,5-bis- · (acylamino) -benzamides of the general formula R ³ NH ^^^ NHR ⁴
in the R and R for hydrogen and / or lower-alkyl groups stand and r3 and R low-alkanol and / or low-alkoxy- ' (lower alkanoyl) groups. mean. 2. Compounds according to claim 1, characterized in that R ³ and R are selected from the group acetyl, propionyl, methoxyacetyl, ethoxyacetyl and methoxypropionyl. 3. Compounds according to claim 2, characterized in that R ¹ fii means. 1 2 that R is hydrogen and R is a lower alkyl group 4. Compounds according to claim 2, characterized in that R ^{1 represents} , .Wasserstoff, R represents a methyl group and R ^ and R stand for an acetyl group. 5. Process for the preparation of 3,5-bis- (acylamino) -benzamides the general formula R ³ WH 709827/1088 ORIGINAL INSPECTED in the 1 2 .R and R for hydrogen and / or lower-alkyl group pen stand and 3 4 R and R represent acyl groups, characterized in that a 3,5-diaminobenzamide is used general formula H ₂ H in the 1 2 R and R for hydrogen and / or lower-alkyl groups stand, reacted with an acylating agent to give the acylated 3,5-diaminobenzamide to build. 6. Process for the preparation of 3- (lower acylamino) -5-amino-2,4,6-trioodbenzamides the general formula CON ^ ^N R ^ H ₂ N "^ S ^ NHR ⁴ in the 1 2 R and R are hydrogen and / or lower-alkyl groups mean and 4 R is a lower alkanoyl or a lower alkoxy Means (lower alkanoyl) group, characterized in that an acylated 3,5-diaminobenzamide the general formula 709827/1088 ORIGINAL INSPECTED CON
t R ³ NH '"* ^Vs - ^ NHR ⁴ in the R, R and R have the meanings given above and R ^{3 is} a lower alkanoyl or lower alkoxy (lower alkanoyl) group, reacts with an iodizing agent in an aqueous medium under acidic conditions. 7. The method according to claim 6, characterized in that 1 2
that R and R from the group acetyl, propionyl, methoxyacet; Ethoxyacetyl and methoxypropionyl are selected. 8. The method according to claim 7, characterized in that R ^{1 is} hydrogen and R ^{2 is} lower-alkyl. 9. The method according to claim 8, characterized in that R ^{2 is} methyl. 10. The method according to claim 9 »characterized in that iodine, iodine monochloride, HJCIp,
Sodium iodine dichloride or potassium iodine dichloride are used. 11. The method according to claim 8, characterized in that iodine, iodine monochloride, HJCLp,
Sodium iodine dichloride or potassium iodine dichloride are used. 12. The method according to claim 11, characterized in that sodium dichloride is used as the iodizing agent. 709827/1088 13. Process for the preparation of 3- (lower acylamino) -5-amino-2,4,6-triiodobenzamide compounds the general formula ,1 J in the R and R for hydrogen and / or lower-alkyl groups stand and R is a lower alkanoyl or lower alkoxy (lower alkanoyl) group means, characterized in that a 3,5-dinitrobenzamide is used general formula R ^{1 C0N} \ 2 O ₂ N ^^ NO ^ 1 2 in which R and R have the meanings given above, hydrogenated to a 3,5-diaminobenzamide of the general formula CON ₂ 1 2
in which R and R have the meanings given above, this compound is acylated to form an acylated 3,5-diaminobenzamide of the general formula 709827/1088 in the R ³ NH 12th
R and R have the meanings given above, and "5 4 and R is lower alkanoyl and / or lower alkoxy (lower alkanoyl) groups mean, to form, and that this acylated 3 »5-diaminobenzamide iodized in an aqueous medium under acidic conditions. 709827/1088