CS216545B2 - Method of production of the n-+l 3-+l 1-3"- oxapentamethylenaminoethylidenamino + p -2,4,6-triiodbenzoyl + p-beta-amino-alpfa methylpropion acid - Google Patents

Description

The invention relates to a new preferred process _; H- [3- (1'-3'-Oxapentamethyleneaminoethylidenamino) -2,4,6-triazole-benzo-yl] -4-amino-α-methylpropionic acid, in which the compound is obtained in excellent yield and with an increased degree of purity.

It is known from German Patent 2,235,935 that 2,4,6-triiodibenzoyl-aminoalkanecarboxylic acid derivatives which contain a substituted amino group at the 3-position of the benzene ring are x-ray contrast agents which allow the visibility of the gallbladder, which are particularly well resorbable and have good resorbability. rapid exclusion, from the body. Of these * compounds, N- [3 '(1'-3' -oxapentamethylenediamethylethylenediamino) - '2,4,6-triiodibenzoyl) -β-amino-α-methylpropionic acid (iomorinic acid) of the formula I is of particular importance,

CO * -NuI 'CH-C //' COOr7y

L il сч

J ^'J c-c-FO) ³ which is used herein as a means of so-called. Cholecystography fast. After oral administration of this compound, preferably in the form of the sodium salt, bile duct images can be obtained after 60 to 90 minutes and bile duct images can be obtained within 5 hours so that the image and its examination can be taken within a day.

For the preparation of the compound of formula (I), according to German Patent Specification No. 2,235,935, 3-amino-2,4,6-triiodobenzoyl chloride is reacted with N-acetylmorpholine and phosphorus oxychloride in boiling and the resulting amidino acid acid chloride is isolated as so- li. This can then be converted to the compound of formula I by liberation of the base by treatment with [beta] -amino-.alpha.-methylpropionic acid esters also under heat and subsequent saponification.

This process has the disadvantage that by reacting 3-amino-2,4,6-triiodobenzoyl chloride with acetylimorpholine, acid-insoluble by-products are formed and, in addition, 3- (1'-3'-oxapentamethyleneaminoethylideneamino) morpholide is formed as another by-product. -2,4,6-triiodobenzoic acid. These impurities can only be separated after the production of the end product, which is very difficult, since the acid of formula I in the contaminated form does not crystallize well or does not crystallize at all, and therefore it is necessary to carry out a loss of purification and repeated evaporation of the mother liquors.

A further variant of the process is the reaction of the alkyl esters of N- (3-amino-2,4,6-triiodobenzoyl) aminoalkanecarboxylic acids with N-acetylmorpholine and phosphorus oxychloride, also at reflux, in the German patent. Although the formation of morpholine can be avoided in this process, the reaction is non-uniform, however, and by-products which are insoluble in acid are also formed. While these can be largely separated by acidification to a pH of 1-1.5, certain amounts of these by-products remain in the product and make it very difficult to purify.

Finally, it is still possible according to German Patent Specification 2,235,935 to produce a compound of formula I at room temperature by reacting N- (3-acetylamino-2,4,6-triiodobenzoyl) -4-amino-α-methylpropioic acid methyl ester with m-oirfoline in However, even more by-products are formed in this process, so that the yield of the pure product is even lower and the purification is even more expensive than other known processes.

Surprisingly, it has now been found that the compound of formula (I) can be produced in excellent purity with a yield of almost 90% when it is reacted with N-acetylmorpholine and phosphorus oxychloride as starting material (not even 3-amino-2,4, 6-triiodibenzoyl chloride or the preformed N- (3-amino-2,4,6-triiodobenzoyl) -. Beta.-amino-.alpha.-methylpropionic acid ester, but using the corresponding nitrile and maintaining certain reaction conditions. of formula I, which is then produced in a very good yield, is practically insoluble in aqueous alkaline solutions and can be precipitated from a water-acid solution without the risk of saponification and thus, unlike the ester, can be cleaned or separated from any insoluble by-products present. acid, but can still be saponified to the acid without any problem, without attacking the amidino group or this causes a noticeable iodine cleavage. Thus, cleaning can be substantially converted to nitrile and has acid of formula I is obtained after saponification so pure that for further purification can seamlessly and without loss, which would be worth mentioning recrystallized.

Accordingly, the present invention provides a process for the preparation of a compound of formula (I) by reacting an N - (3-amino-2,4,6-tri-benzoyl) -β-amino-α-methylpropionic acid derivative with N-acetylmorpholine in the presence of phosphorus oxychloride and a solvent. which is characterized in that it uses (N- (3-amino-2,4,6-triiodobenzoyl)) as a derivative of N- (3-amino-2,4,6-triiodobenzoyl) -β-amino-α-methylpropionic acid The compound is mixed at a temperature between 0 ° C and 10 ° C, the reaction is carried out at temperatures between 10 ° C and the boiling point of the reaction mixture, the resulting reaction mixture is taken up with water or any solvent present during or after evaporation of the solvent. the insoluble fractions are separated from the acid solution obtained and, by alkalization to a pH of at least 8, the nitrile of the formula P is precipitated,

The nitrile is then converted to the free acid by saponification with alkaline acidic agents.

In carrying out the process of the invention, it has proven expedient to use N-acetylmoirfoline in excess of N- (3-amino-2,4,6-triiodobenzoyl) -4-amino-α-methylpropionitrile. This excess should not be too small and preferably is between 1.5 and 3 moles, with better results also achieving better results. Although the reaction is also feasible without this excess, a relatively large amount of by-products is nevertheless obtained which, although they can be well separated, entails a reduction in yield. Favorable results are obtained when the molar ratio of nitrile to acetylmorpholine is 1: 3.

In addition, it is preferred to use phosphorus oxychloride in excess; in particular when the molar ratio of nitrile to acetylmorpholine is less than 1: 3. This excess phosphorus oxychloride is expediently to be 2 to 6 mol per 1 mol of nitrile.

Particularly good results, i.e. yields above 90% nitrile and below 5% by-products, are obtained when the molar ratio of nitrile: acetylmorpholine: phosphorus oxychloride is 1: 3: 2 to 6, with a molar ratio of 1: 3: 6 best results. Very good results are obtained with a molar ratio of nitrile to acetylmorpholine of 1: 2 when 6 moles of phosphorus oxychloride per 1 mol of nitrile is used.

It is advantageous to mix the reactants with each other if the reaction temperature does not exceed 5 ° C. It is also favorable for the next reaction if the temperature reaches maximum room temperature, since then the yield is particularly favorable. However, it is also possible to carry out the reaction at a higher reaction temperature, which is especially recommended when shorter reaction times are desired.

The fact that besides the nitrile of formula (II) also gives rise to by-products, although it affects the yield, but does not affect the process or purity of the final products of formula (I). This is because the nitrile of formula (II) excellent clean. This means that even when carrying out the process under conditions where more than 5% by-products are obtained, there are no difficulties in purifying the nitrile, and therefore the purity of the reaction product of formula I is still satisfactory.

The reaction of N- {3-amino-2,4,6-triiodobenzoyl] -β-amino-β-aminoethylpropionitrile with N-acetylmorpholine and phosphorus oxychloride is carried out in an inert reaction medium, preferably in an inert organic solvent. Since -nitrile, which serves as the starting material, is hardly soluble in conventional organic solvents, it is generally employed in solvents in which the insoluble complex consisting of N-acetylmorpholine and phosphorus oxychloride is, however, the nitrile is soluble in such solvents. Such solvents are, for example, dioxane, tetrahydrofuran, acetonitrile, and chlorinated hydrocarbons such as chloroform or methylene chloride. Surprisingly, although the heterogeneous phase is used, the yield is very good.

Solubility of the complex. Furthermore, acetyl morpholine and phosphorus oxychloride are not a prerequisite for a successful process according to the invention. The reaction also proceeds smoothly in organic solvents such as aromatic hydrocarbons, in particular toluene, in which the complex of acetylmorpholine and phosphorus oxychloride is also not soluble, but only suspended therein. The reaction can also be carried out in excess phosphorus oxychloride as solvent. It is expedient to further purify the acidic solution formed by removing the reaction product with water by adding activated carbon. The precipitation of the base of formula (II) is then effected by alkalinizing with each water-soluble base which is sufficiently alkaline to ensure that the pH is reached at least 8. Preferably, ammonia is used. If several by-products are present, repeated purification can be easily and / or lost by dissolving the nitrile of the formula II once more in dilute acid, or treating it again with activated carbon and reprecipitating - alkalization.

The saponification in this way in the pure form of the nitrile II obtained surprisingly proceeds quite spontaneously completely smoothly. It can be carried out by the action of concentrated inorganic acids such as hydrochloric acid or sulfuric acid. However, it is also possible with alkaline agents, for example by treatment with alcoholic-aqueous alkali metal hydroxides such as sodium or potassium hydroxide. Finally, however, the corresponding imidoester can also be produced first by treatment with acids in an alcoholic medium, for example by treatment with methanolic hydrogen chloride, and cleavage with water. From the solution after saponification, the free compound of the formula I, which has an amphoteric character, is best precipitated by precipitation at the isoelectric point and is obtained in almost quantitative yield in pure form.

N- (3-Amino-2,4,6-thiiodobenzoyl) - (Sarnino-α-methylpropionitrile), which is required as a starting material, is obtained in a simple manner by acacylation of β-aminoisobutyric acid nitrile with 3-aminoQ-2 4,6-diisobenzoyl chloride in yields above 90%. The ammonium butyric acid nitrile is also produced by the addition of ammonia to the methacrylonitrile also in a simple manner and can be obtained by distillation easily in a pure state.

The process of the present invention is illustrated by the following examples, but not by way of limitation.

He did

To 183.6 g (1.2 mol) of phosphorus pentachloride in 500 ml of chloroform at 0 DEG C. was added 77.4 g (0.6 mol) of N-acetylmorpholine. In this case, the temperature rises to about 8 ° C. After the temperature was lowered again to 0 ° C, 116.2 g (0.2 mol) of N- (3-amino-2,4,6-triiodobenzoyl) -4-amino-α- of methyl pionopropionitrile, and then the suspension is stirred without further cooling.

After 40 hours, the -suspension in chloroform is poured into 800 ml of water, so that the hlooroform is continuously distilled off and a clear aqueous phase is formed. To remove the last chloroform residue, the aqueous solution is boiled briefly. The solution is then cooled, filtered through activated carbon and the acidic solution is first adjusted to pH 6 by addition of 40% aqueous sodium hydroxide and then made alkaline with concentrated aqueous ammonia. The nitrile of formula II, which is partially eliminated in the oily form, by heating the aqueous-ammoniacal solution to 85 ° C with vigorous stirring, solidifies for a short time or becomes filterable. Filtered, the product is redissolved in 1.2 liters of water which. It contains 0.4 mol of hydrochloric acid, activated charcoal is added, the mixture is then filtered, and the filtrate is basified with ammonia as described above and the desired product precipitates.

-SE- give 137 g of N [3- _I (l "-3" -Qxapenta.methylenamin · Qethylidenamino) -2,4,6-trijQdbenzoyl] -S-amin0-and-methylpropionitrile -o mp 129- 130 ° to C, ie 98.9% - theory.

137 g of the thus prepared N- [3- (4- (4-pentamethyleneaminoethylideneamino) -2,4,6-triiodobenzoyl) -N-amino-α-methylpropionitrile] are dissolved in 300 ml of concentrated hydrochloric acid and the solution is heated to 80 °. C. After -22 hours the hydrolysis is complete and the aqueous-acidic solution in hydrochloric acid is evaporated in vacuo. The residue was dissolved in aqueous sodium hydroxide and the insoluble material was filtered off. Acid precipitates from the filtrate by adjusting the pH to 4.5. 123 g (87.6% of theory) of N- [3-] are obtained.

- (1‘-3'-Oxapentamethyleneaminoethylidenamimo) -2,4,6-triiodobenzoyl) -β-amino- α-methylpropionic acid.

Concentration of the mother liquor yielded an additional 16.2 g of acid (11.5% of theory). After recrystallization of the combined products from methanol, 124 g of crystalline acid having a melting point of 202 DEG-205 DEG C., i.e.

87.2% of theory based on N- (3-amino-2,4,6-tri-iodobenzoyl) -β-amino-α-imethylpropionitrile.

The N- (3-Amino-2,4,6-triiodobenzoyl) -β-amino-α-methylpropionitrile, which is needed as a starting material, is prepared as follows:

106.6 g (0.2 mol) of 3-amino-2,4,6-triiodaminobenizoic acid chloride are boiled in 500 ml of chloroform with 17.6 g of β-aminoisobutyric acid nitrile and 21.2 g of triethylamine under reflux for several hours. During the heating process, N- (3-amino-2,4,6-triiodobenzoyl) -β-amino-α-methylpropionitrile begins to crystallize. To complete the crystallization, 20 ml of chloroform was distilled off from the reaction mixture, then the mixture was allowed to stand at room temperature. After filtration, 108.4 g (93.3%) of the nitrile is obtained. An additional 6.3 g (5.4%) of the starting material are obtained from the mother liquor after washing with chloroform with water followed by concentration to a volume of 40 ml. Mp 187 ° C.

Example 2

183.6 g (1.2 mol) of phosphorus oxychloride and 77.4 g (0.6 mol) of N-acetylmorpholine were added at 0 ^; ° C is added to 500 ml of dioxane and then a solution of 116.2 g (0.2 mol) of N-

- (3-amino-2,4,6-triiodobenzoyl) -β-amino-α-methylpropionitrile in 500 ml dioxane.

After stirring overnight, the dioxane is distilled off under vacuum, the residue is taken up with about 1 liter of water, the solution is filtered over activated carbon and N- [3- (1'-3'-oxapentamethyleneaminoethylideneamino) -2,4,6-triiodobenzoyl] -β The amino-α-methylpropionitrile is precipitated by the addition of ammonia at pH 8.5. The still wet product was dissolved in 1.2 L of 1N hydrochloric acid solution after filtration and the solution was filtered through charcoal. From the now clear filtrate, the nitrile is reprecipitated with hydroxide and filtered off. There were obtained 121 g (87.5% of theory] N- [3- (l-3 "-oxapentamethylenaminoethylidenamino) -2,4,6-trijO'dbeinzoyl] - _and 3-amino-.alpha.-methylpropionitrile of melting point 129 DEG 130 [deg.] C.

The saponification is carried out as described in Example 1.

Example 3

To 250 ml of phosphorus oxychloride, 19 g of N-acetylmorpholine was added at 0 ° C. The temperature rises to 10 ° C through continued cooling. After 5 minutes, 29 g of N- (3-amino-2,4,6-triiodobenzoyl) -4-amino-α-methylpropionitrile was added with further cooling at 5 ° C with stirring. The reaction mixture was further stirred at 0 ° C overnight to give an almost clear solution.

For working up, phosphorus oxychloride is distilled off as well as possible and the residue is dissolved in 150 ml of chloroform and this solution is poured into 300 ml of water. Then, the reaction mixture is further processed as described in Example 1.

33 g (95.4% of theory) of N- [3- (1'-3'-oxapentamethyleneaminoethylideneamino) -2,4,6-triiodobenzoyl) -β-amino-α-methylpropionitrile are obtained, m.p. 129-130 °. C.

The saponification is carried out as described in Example 1.

Example 4

To 46 g of phosphorus oxychloride in 200 ml of toluene, 19.4 g of N-acetylmorpholine are added at 0 DEG C. with cooling. After a short time a white precipitate forms in the solution. 29 g of N- (3-amino-2,4,6-tri-iodobenzoyl) -β-amino-.alpha.-methylpropionitrile are then added with stirring and the reaction mixture is allowed to stir at 20 DEG C. for 40 hours. The oily reaction product thus obtained is taken up in 400 ml of water and the slightly turbid solution is filtered over activated carbon. N- [3- (1‘-3'-Oxapentamethyleniaminoethylenenamino) -2,4,6-triiodobenzoyl] -β-amino-α-methylpiropionitrile precipitates from the clear acid filtrate by adjusting the pH to> 8. 33.2 g (96%) of the theory of the reaction product are obtained. Mp 129-130 ° C.

The saponification is carried out as described in Example 1.

Example 1 a d 5

183.6 g (1.2 mol) of phosphorus oxychloride are mixed as described in Example 1 'at 0 ° C with 77.4 g (0.6 mol) of N-acetylmorpholine and 116.2 g (0.2 mol) Of N- (3-amino-2,4,6-triiodobenzoyl) -O-amino-.alpha.-methylpropionitrile, and then the reaction mixture was refluxed for 18 hours. The work-up is carried out as described in Example 1.

121.3 g of N- [3- (1H-3'-oxapeintamethylenamiinoerthylideneamino) -2,4,6-triiodobenzoyl] -4-amino-.alpha.-methylpropionitrile are obtained, i.

87.6% of theory.

Mp 129-130 ° C.

The saponification is carried out as described in Example 1.

Example 6

34.5 g of N- [3- (1'-3'-oxapentamethyleneaminoethylideneamino) -2,4,6-triiodobenzoyl] -β-amino-α-methylpropionitrile, obtained according to any of the preceding examples, are dissolved hot in The reaction mixture was boiled for 2 hours after addition of 20 g of 20% sodium hydroxide

under · reflux condenser. Then the alcohol is distilled off, the residue is diluted with water to a content of 500 ml and hydrochloric acid is adjusted to pH 1. The flakes are separated. They are filtered out. The acid is precipitated from the clear filtrate by adjusting the pH to 4.5 and distilling off. After recrystallization. 25 g of pure crystalline N- (3- (3-oxo-pentamethyleneaminoethylideneamino) -2,4,6-triiodobenzoyl) -1,3-amino-α-methylpropionic acid are obtained from methanol. m.p. 202-205 ° C, which is 72% of theory based on N- (α-amino-β-triiodobenziayl) -β-α-methylpropionitrile, if nitrile was produced according to Example 1.

Example 7

N- [3 - (.alpha.,. Beta.-alpha-pentamethyleneamethylethyl amide) -2,4, 6-tri-iodobenzoyl] -βaamido-.alpha.-methylpropionitrile, prepared according to any one of Examples 1 to 5. The reaction mixture was boiled in 150 ml of 10N methanolic hydrogen chloride at reflux for 2 hours. The methanolic hydrochloric acid is distilled off completely and the residue is taken up in 300 ml of water, the solution is boiled briefly and the insoluble matter is filtered off. By correcting the pH to 4.5, the acid precipitates and is isolated. Recrystallization from methanol gave 24.2 g of N- [3- [1'-3'-oxapentamethyleneainoethylideneamino] -2,4,6-triiodobenzoyl] -7 (-amino-α-methylpropionic acid), m.p. 202-205. [Deg.] C. The yield is based on N- (3-amino-2,4,6-triiodomethyl) -4-amino-.alpha.-methylpropionitrile, assuming the preparation of the nitrile according to Example 1, 78. % theory.

Example 8

To illustrate how the excess of N-acetylmorpholine and / or phosphorus oxychloride used influences the results of the process, the molar ratios of the components vary in 12 separate experiments, the other reaction conditions being as described in Example 1. The test results are summarized in the following table.

Table molar ratio yield of nitrile of formula II

nitrile : acetylmorpholine: РОС1з and creation of by-products (VP) nitrile of formula II (IN P) 1 1 1 or 6 60 0/0 (27 θ / o VP) 1 1.5 3 68% (25% VP) 1 2 2 79% (16% VP) 1 2 3 91% (7 0/0 VP) 1 2 6 95% (3% VP) 1 3 1 83% (17% VP) 1 3 2, 3, 4 or 5 96 to 97% (3 to 2% VP) 1 : 3: : 6 98% (1% VP)

SUBJECT OF THE INVENTION

Claims (6)

A process for the preparation of N- [3- (T ‘[3'-oxapeinta'me [thylenaminoethylidenamrno) -2,4,6-triiodobenzoyl] - (- 011110 ---- 0-propionic acid moieties of formula 1) N ¹¹ / —k HC-CN 0 ³ / zoyl-4-amino-4-methylpropionic acid with N-acetylmorpholine in the presence of phosphorus oxychloride and a solvent, characterized in that, as a derivative of N- (3-amino-2,4,6-tri-iodobenzyl) N - (3-amino-2,4,6-tri-iodobenzoyl) - [beta] -aminoethylpropionate nitrile, the reactants are mixed at a temperature of 0 ° C to 0 ° C. 10 ° C, the reaction is carried out at a temperature between 10 ° C and the boiling point of the reaction mixture, the obtained reaction mixture is taken up with water during or after evaporation, or any insoluble matter present is separated from the resulting acid solution and basified to pH at least 8 the nitrile of formula (11) is reacted by reacting the N- (3-amino-2,4,6-triiodo [beta] 165,545 derivative which is isolated and optionally purified, whereupon the nitrile is converted by saponification with alkaline or acidic agents to the free acid. 2. The process according to claim 1, wherein the amount of N-acetylmorpholine is used in an amount of 1.5 to 3 moles per mole of N- (3-amino-2,4,6-). 3-amino-.alpha.-methylpropionitrile. 3. The process according to claim 1, wherein the phosphorus oxychloride is used in an amount of 2 to 6 moles per 1 mol of N- (3-amino-2,4,6-triiodobenzoyl) - / 3-amino. -α-methylpropionitrile. 4. The process according to claim 1, wherein 3 mol of N-acetylmorpholine and 2 mol of N- (3-amino-2,4,6-triiodobenzoyl) -4-amino-.alpha.-methylpropionitrile are used. up to 6 moles of phosphorus oxychloride. 5. The process according to claim 1, wherein 1 mol of N- (3-amino-2,4,6-triiodobenzoyl) - [S-amino-.alpha.-methylproplonitrile is 2 moles of acet-acetylmorpholine and 6 moles. phosphorus oxychloride. 6. A process according to claims 1 to 5, characterized in that the reactants are mixed at a temperature of from 0 DEG C. to 5 DEG C. and reacted at temperatures not exceeding room temperature.