HU180185B - Process for producing 3-square bracket-3-aracket-1-morpholino-ethyliden-amino-bracket closed-2,4,6-triiodo-benzoyl-amino-square bracket closed-2-methyl-propionic acid - Google Patents

Abstract

A process for the preparation of N- & 3- (1'-3 "-oxapentamethyleneamino-ethylideneamino) -2,4,6-triiodobenzoyl-beta-amino-alpha-methylpropionic acid (Iomoric acid) of the formula I which comprises N- (3 -Amino-2,4,6-triiodobenzoyl) -beta-amino-alpha-methylpropionitrile with N-acetylmorpholine in the presence of phosphorus oxychloride and a solvent and reacting while nitrile of formula II isolated by alkalization, optionally purified and finally this nitrile by Saponification in acidic or alkaline medium in the free IomorinsÄure überfuehrt.

Description

Process for the preparation of 3- (3- (1-morpholinoethylideneamino) -2,4,6-triiodobenzoylamino] -2-methylpropionic acid

The present invention relates to a new preferred process for the preparation of J-F1-Z1-morpholloethylideneamino-2,4,4-triiodobenzeneamino-2-ethyl-propionic acid in good yield and high purity.

German Patent No. 2,235,955. It is known that derivatives of 2,4,6-triiodobenzoylaminoalkane carboxylic acids having an amino group substituted at the 3-position of the benzene ring are X-ray contrast agents for visualization of the gallbladder. they are particularly good for resorbability and rapid elimination from the body. Among them, in particular the compounds can be represented by Formula I 5- [y5 '' / L ^{'mor; Co l- amino} "®' ^fcl ^ ^i-amino OEN / -2,4,6-triiodo-benzoyl-2 amlnol -methylpropionic acid (Iomorinic acid) has become important, which is used as a so-called rapid cholecystography. 60-90 minutes after oral administration of this compound, preferably in the form of its sodium salt, images of the bile ducts and within 5 hours of the gallbladder are obtained, so that one day may be taken and examined.

For the preparation of the compound of formula I, U.S. Pat. According to the German patent, 3-emino-2,4,6-triiodobenzoyl chloride is reacted with N-acetylmorpholine and phosphoryl trichloride under heating in chloroform and the acid chloride in which the amidino group is formed is isolated as a salt. This can then be converted to the compound of formula I after liberation of the base and reaction with J-amino-2-methylpropionic acid esters also under heating and finally saponification.

-1180185

Heck of process has the disadvantage that 3- acid-insoluble byproducts are formed and to which a further by-product, 3- / l-morpholino-ethylidene the reaction with ^the amino-2,4,6-Eino tr1jód chloride in acetyl morfol1nnal Morpholide of / -2,4,6-triiodobenzoic acid. These impurities can be separated only after the final product has been prepared, which is very difficult because the acid of formula I in the contaminated form does not crystallize badly or not at all and the purification itself is very lossy and requires multiple evaporation of the mother liquors.

Further, in the above-mentioned German Patent, N- (3-Amino-2,4,6-triiodobenzoyl) -amino-α] -carboxylic acid alkyl esters of N-acetylmorphine and majorioryl reaction with trichloride, also at the temperature of waxing. In this procedure, the formation of morpho-oil cl is avoided in the brain, however, the reaction does not proceed uniformly, and here again acid-insoluble by-products are formed. Although they can be largely removed by acidification to a pH of 1-1.5, they still retain some by-product in the product and make it very difficult to purify.

Finally, no. According to a German patent patent, the preparation of the compound of formula I is carried out at room temperature with 3- (3-acetylamino) -2,4,6-triodo-benzoylamino-2-methyl-propionic acid methyl ester with moxpholine in the presence of phosphorus pentachloride. however, more by-products are formed in this reaction such that the yield per pure product is even lower and the purification more laborious than other known processes.

Surprisingly, it has been found that the compound of Formula I itself can be prepared in excellent purity in a yield of about 90% if the reaction with IT-acetylmorpholine and phosphoryl trichloride does not yield 3-amino-2,4, Starting from 6-triiodo-benzoyl chloride, not from the previously prepared 3- / 3-amino-2,4,6-thioiodobenzoyl-amino-2-methylpropionic acid ester, but from the corresponding nitrile , and certain procedural conditions are followed. The nltrile of the acid of formula I which is produced in very good yields is practically insoluble in aqueous alkaline solutions and can be precipitated from the aqueous acidic solution without the risk of hydrolysis, and thus can be separated from the acid-insoluble byproducts without significant damage to the amidino group and detectable iodine cleavage. Thus, the purification is substantially pure to the nitrile, and after acidification of the acid of Formula I, it becomes so pure that it can be recrystallized without further delay and without significant loss for further purification.

The present invention therefore relates to a process for the preparation of a compound of the formula I in the presence of N-acetylmorpholine, a derivative of 3- [3-amino-2,4,6-thioxo-benzoylamino] -2-methyl-propionic acid, and a solvent. reacting, characterized in that the ^{3/3, no} ~ ⁿ i '2,4,6-triiodo-benzoyl-amino / -2-methyl-propionic acid derivative of the 3/3-amino-2,4 6-Triiodobenzoylamino / -2-methylpropionitrile was used and the reaction partners were mixed at a temperature of 0 ° C to 10 ° C, at a temperature between 10 ° C and the boiling point of the reaction mixture. dissolve in water during or after distillation of the solvent, optionally any insoluble matter is separated from the resulting acidic solution, and the nltxyl of Formula II is precipitated, alkalinized to at least pH 8, isolated and optionally purified, followed by treatment with nitrile using alkaline or acidic reagents v gzett elszappanoaitáasal converted to the free acid.

In carrying out the process of the present invention, it has been found advantageous to use N-acetylmorpholine in an excess relative to 3- [3-amino-2,4,6-triiodobenzoylamino] -2-methylproplorjutril. This excess should not be too small, preferably from 1.5 to 3 moles, but larger excess results in better results. The reaction can be carried out without excess, but this results in a relatively large amount of by-products which, although well separated, causes a loss in yield. The best results are obtained when a molar ratio of 1: 3 nitrile: acetylmorpholine is chosen.

In addition, it is also advantageous to use an excess amount of phosphoryl-trichloride, especially when the molar ratio of nitrile: acetylmorpholine is below 1: 3. This excess phosphoryl trichloride should preferably be from 2 to 6 moles per mole of nitrile.

Particularly good results, namely yields greater than 90% by weight and nitrate by-products below 5% when nitrile is used when using a molar ratio of 1: 3: 2-6 nitrile: acetylmoroline: phosphoryl trichloride, are obtained with a molar ratio of 1: 3: 6. Very good results are also obtained with a molar ratio of nitroxyljacetylmorpholine of 1: 2 when using 6 moles of phosphoryl trichloride per mole of nitrile.

If the reaction is carried out at room temperature, the yield is particularly good. However, it is also possible to react at a higher reaction temperature, which is particularly desirable if shorter reaction times are desired.

The fact that by-products are precipitated in addition to the nitrile of Formula II has an impact on the yield, but is not relevant to the success of the process or the purity of the final Formula I product. Mainly because the nitrile of Formula II has excellent purity due to its solubility properties. This means that even when carrying out the process of obtaining more than 5% of a breast breast coin, the purification of the nitrile does not present any difficulty, and therefore the purity of the final product of formula I is satisfactory.

Reaction of 3- / 3-amine o-2,4,6-triiodobenzene-2-amino / -2-methylphthalonitxyl with N-acetylmorpholine and phosphoryl trichloride in an inert reaction medium , preferably in an inert organic solvent. Since the starting nitrile is poorly soluble in the organic solvents used, most of the solvents used are those in which the complex formed by N-acetylmorpholine and phosphoryl trichloride itself is insoluble, but the nitrile is. Examples of such solvents are dioxane, tetrahydrofuran, aonetonitrile and chlorinated hydrocarbons such as chloroform or dichloromethane. Surprisingly, despite working in the heterogeneous phase, the yield is very good.

Accordingly, the solubility of the complex formed of acetylmorpholine and phosphoryl trichloride has no effect on the success of the process of the invention. The reaction proceeds smoothly in organic solvents such as aromatic hydrocarbons,

-3180185 especially toluene, in which the complex formed from acetylmorpholine and phosphoryltrichloride is not soluble but can only be suspended. The reaction may also be carried out in excess of the solvent used as a solvent. It is preferable to purify the acidic solution, which is formed when the reaction product is dissolved in water, by addition of activated carbon. The precipitation of the base of formula II can then be carried out by treatment with any base which is sufficiently alkaline to ensure a pH of at least 8. Ammonia is preferably used. If multiple by-products are present, multiple purifications can be made without difficulty or loss, if the nitrile of formula II is redissolved in a dilute acid, or treated with ^{4 I of} carbon and precipitated again by alkalization.

Surprisingly, the saponification of nltril of formula II obtained in pure form is completely smooth. This can be done with concentrated inorganic acids such as hydrochloric acid or sulfuric acid. However, it is also possible to use alkaline reagents such as alcoholic-aqueous alkali metal hydroxide solutions, such as sodium hydroxide or potassium hydroxide solution. Finally, the corresponding imino ester can be first prepared with acids in an alcoholic medium, such as methanolic hydrochloric acid, and cleaved by treatment with water. From the saponification solution, the free compound of formula I, which is amphoteric, is best precipitated at the isoelectric point, and is thus obtained in pure form in near quantitative yield.

The starting 3- (3-amino-2,4,6-triiodobenzoylamino / -2-methylpropionitrile) is simply 3-amino-2-methylpropionitrile J-amino-2,4,6-. by acylation with triiodobenzene chloride in over 90% yield. 3-Amino-2-methylpropionitrile is also prepared by simple addition of ammonia to methyl acrylonitrile and is easily obtained by distillation.

Example 1

183.6 g (1.2 mol) of phosphoryl-trichloride in 500 ml of chloroform at 0 ^D C are mixed with 77 x 4 g / 0.6 mol of N-acetylmorpholine. The temperature rises to about 8 ° C despite further cooling. After the temperature again returns to 0 ° C, 116.2 g (0.2 mol) of 3/3-amino-2,4,6-triiodobenzoylamino / -2-methylpropionitrile is added, followed by the suspension was stirred without further cooling.

After 40 hours, the chloroform suspension is poured into 800 ml of water at a rate such that the chloroform is continuously evaporated to form a clear aqueous phase. The aqueous phase is refluxed for a short time to remove the final chloroform residues. After cooling, filtering with charcoal, the acidic solution was first adjusted to pH 6 with 40% aqueous sodium hydroxide solution and then basified with concentrated aqueous ammonium hydroxide. The partially oily trinyl II Formula II is solid and can be filtered after heating the aqueous ammonia solution to 85 ° C and vigorous stirring. The filtered product is redissolved in 1.2 L of water containing 0.4 M hydrochloric acid, decolorized with activated carbon, basified with ammonia as described above, and precipitated.

137 g of m.p. 129-130 ° C are obtained with a yield of 3-9- (1-niorpholinoethyleneamino) -2,4,6-triiodobenzoyl-amine / -2-methylpropionyltril having a theoretical yield of 98-9%. -the·

137 g of the thus obtained 3- [3- (1-morphollno-6-ethylideneamino) -2,4,6-triiodobenzene-amino] -2-methylpropionyltril (300 ml) were concentrated.

-4180185 was dissolved in hydrochloric acid and the solution was heated to 80 ° C. Hydrolysis is complete after 2 hours and the aqueous hydrochloric acid solution is concentrated in vacuo. The residue was dissolved in aqueous sodium hydroxide solution and filtered from the insolubles. From the filtrate, the acid is precipitated by adjusting the pH of the solution to 4.5. 12) g (87.6% of theory) of (5-Z5 - [-] - morpholinoethylenediamino) -2,4,6-triiodobenzoyl-amino-7-methylpropionic acid is obtained.

Further digestion of the mother liquor yielded an additional 16.2 g / 11.5% acid. Recrystallization of the combined products from methanol gives 124 g of pure crystalline acid, m.p. 202-205 ° C, 87.2% of theory of N- [3-amino-2,4,6-triiodobenzoyl]. calculated for amno-2-methylproplonitrile.

The starting material N- [3-amino-2,4,6-triiodobenzene-amino] -2-methyl-11-proponitrile was prepared as follows:

106.6 g (0.2 M) of 3-amino-2,4,6-triiodobenzene chloride in 500 ml of chloroform with 17.6 g of 3-amino-2-methyl-proponitrile and 21.2 g of triethylamine for several hours. boil under reflux. During heating, 3- [3-amino-2,4,6-triiodobenzoylamino] -2-methylpropionyltrl [11] begins to crystallize. To complete the crystallization, 200 ml of chloroform was distilled off from the reaction mixture and then allowed to stand at room temperature. Filtration gave 108.4 g (95.5%) of nitrile. The mother liquor was washed with chloroform with water and then concentrated to a further 6.3 g (5.4%). Melting point: 187 ° C.

Example 2

183.6 g (1.2 mol) of phosphoryl trichloride and 77.4 g / 0.6 mol of N-acetylmorpholine are added at 0 ° C to 500 ml of dioxane and then 116.2 g / 0.2 mol / 3- / 3 ~ ^& IALN-2,4,6-triiodo-benzoyl-amino / -2-methyl-propionitrile in 500 ml dloxánnal solution.

After stirring overnight, the dioxane was distilled off in vacuo, the residue was dissolved in about 1 liter of water, filtered through charcoal and filtered with 3 - [3- / 1-α-morpholinoethyleneamino] -2,4 * 6-triiodobenzoylammonium -2-Methylproplonitrile was precipitated by addition of ammonia at pH 8.5. After filtration, the still wet product was dissolved in 1.2 L of 1N hydrochloric acid and filtered with activated charcoal. From the almost pure filtrate, the nitrile was again precipitated with alkali and filtered. Yield: 121 g (m.p. 129-130 ° C) of the theoretical 87.5% -5- (1-morpholinoethylideneamino) -2,4,6-triiodobenzoylamino-2-methylpropionitrile.

The saponification is carried out as described in Example 1.

Example 3

250 ml of phosphoryl trichloride are mixed with 19 g of N-acetylmorpholine at 0 ° C. Despite cooling, the temperature rises to 10 ° C. After 5 minutes with additional cooling, 29 g of 3- (5-amino-2,4,6-triiodobenzoylamino) -2-methylpropyltritrile was added with stirring at 5 ° C. The reaction mixture was stirred at 20 ° C overnight until an almost clear solution was formed.

During work-up, as much as possible, the phosphoryl trichloride is distilled off in vacuo, and the para-residue is dissolved in 150 ml of chloroform and poured into 300 ml of water. Then it is

As described in Example 1, it will be further processed.

Thus, 55 g (95.4% of theory) of 5- [5- [5- (1-morpholinoethylideneamino) -2,4,6-triiodobenzoylamino] -2-methylpropionitrile

Mp 129-130 ° C.

The saponification is carried out as described in Example 1.

Example 4 Phosphoryl trichloride (g) in toluene (200 ml) was cooled to 0 ° C with 19 g of 4-acetylmorpholine under cooling. After a short time a white precipitate formed in the solution. After stirring, 29 g of 3- [3-anilno-2,4,6-tr] iodo- _T- benzoylamino / -2-methylpropyl] -tril are added and the mixture is stirred for another 40 hours at 20 ° C. The resulting oily reaction product was dissolved in water (400 mL) and the slightly cloudy solution was filtered off with activated charcoal. After adjusting the pH to 8 or higher, the pure acidic filtrate precipitates 3 [beta] - [3-morpholinoethylidene] amino-2,4,4-triiodobenzoylamine [beta] -2-methylpropionitrile. This gives 33 * 2 g, 96% of theory. Melting point: 129-130 ° C.

The saponification is carried out as described in Example 1.

5 «Example

183.6 g / l * 2 moles of phosphoryl trichloride, as described in Example 1, at 0 ° C with 77.4 g / 0.6 moles of U-acetylmorpholine and 116.2 g / 0.2 moles It is mixed with N, N-amino-2,4,6-triiodobenzoylamino / -2-methylpropionitrile and refluxed for 18 hours. The processing is broken as described in Example 1.

There was thus obtained 121.3 g of 3-0- (1-niorpholinoethylideneamino) -2,4,6-triiodobenzeneamino-5-methylpropionitrile (87.6% of theory).

129-130 ° C.

The saponification is carried out as described in Example 1.

Example 6

34.5 g of 3-Z3- (1-morpholinoethylideneamino) -2,4,6-triodobenzoylamino] -2-methylproponitrile, obtained according to one of the preceding examples, are dissolved in 1 liter of 96% hot. ethanol, and after adding 20 g of 20% sodium hydroxide solution, reflux for 2 hours. The ethanol is then distilled off, the residue is diluted to 500 ml with water and the solution is brought to pH 1 with hydrochloric acid. The fine flakes are then filtered off. From the pure filtrate, the acid is precipitated by adjusting the pH to 4.5 and filtered. After recrystallization from methanol, 25 g of pure crystalline 3-0- (1-morpholinol) m.p. 202-205 ° C are treated with 11-lindenamino / -2,4,6-trifluoro-benzoylamino. -2-methylpropionic acid is obtained, which is 72% of the theoretical yield, based on N- (3-amino-2,4,6-triiodobenzoylamino) -2-methylpropionitrile, if the nitrile is Example 1 ·

Example 7 g of 3- [4- (1-morpholinoethylidene) amino] -2,4,6-triiodobenzeneamine-2-methylpropionitrile, prepared according to one of Examples 1-5, in 150 ml. Reflux in methanolic hydrogen chloride solution for 2 hours. The methanolic hydrochloric acid was completely distilled off and the residue was dissolved in 300 ml of water, refluxed for a short time and the insoluble was filtered off. The acid is precipitated by adjusting the pH to 4.5 and isolated. recrystallization from methanol

After -6180185, 24.2 g of 3- (N- [1-morpholinoethylideneamino] -2,4,6-triiodobenzenylamino] -2-methylpropionic acid are obtained, m.p. 202-205 d. The yield is 78% of theory based on the preparation of nitrile according to Example 1, based on 3- [3-amino-2,4,6-triiodobenzenylamino] -2-methylpropionyltril.

Example 8

In order to demonstrate the effect of the procedure on the use of excess N-acetylmorpholine and / or phosphoryl trichloride, the molar ratios of the reaction partners were varied in 12 experiments, and the process conditions were as in Example 1. The results are summarized in the following table.

Table 1

Molar ratio of ntril to acetylmorpholine: POClj

1 1 1 i 1 or 6 1 1.5 3 1 2 t 2 1 t 2 : 3 1 2 1 6 1 3 i 1 1 3 : 2,3,4 or 5 1 3 : 6

Yield to nltrll of formula II and by-product image

collapse / MT / 60 % / 27 % MT / 68 % / 25 % MT / 79 % / 17 % MT / 91 % / 7 % MT / 95 % / 3 % MT / 83 % / 16 % MT / 96-97 % / 3-2% MT / 98 % / 1 % MT /

Patent claims

Claims (6)

Patent claims A process for the preparation of 3-0- (1-morpholinoethylenediamino) -2,4,6-triiodobenzeneamino] -2-methylpropionic acid of the formula I 5- [3-Amino-2,4,6-triiodo by reacting a derivative of benzoylamino-2-methylpropionic acid with N-acetylmorpholine in the presence of phosphoryl trichloride and a solvent, characterized in that the 3- / 3-amino-2,4,6-triiodobenzoyl- 3- (3-Amino-η-2,4,6-iodo-dicollol-amino) -2-methyl-propionitrile was used as the derivative of amino-2-methyl-11-propionic acid; The reaction mixture is taken up with water during or after distillation of the solvent, the optional insolubles are removed from the resulting acidic solution and brought to a pH of at least 8 ° C. by alkalinization, precipitate the nltril of Formula II, separate, and purify if necessary and then converting this nitrile to the free acid by saponification with alkaline or acidic agents. 2. The process according to claim 1, wherein the N-acetylmorpholine is used in an amount of 1.5-3 µmol to form 3- [3-amino-2,4,6-triiodobenzenyl] amino] -2 per mole of methyl propionitrile, The process of claim 1 and 2, wherein the phosphoryl trichloride is 2-6 -7180185 moles. is used in the amount per mole of 3- [3-amino-2,4,6-t-iodo-benzoylamino] -2-methyl-propionyltril. 4. The process according to claims 1 to 3, wherein 3 moles of N-acetylmorpholine and 2-6 moles of N-acetylmorpholine per mole of 3- [3-amylno-2,4,6-triiodobenzoylamino] -2-ethylpropyltritrile are used. moles of phosphoryl trichloride are used. 5. A process according to claims 1 to 3, characterized in that 2 moles of N-aoethylmorpholln and 6 moles of phosphorus 11- are added per mole of 3- [3-amino] -no-2,4,6-triiodobenzoylamino-2-methylpropionyltril. using trichloride. 6. A process according to any one of claims 1 to 4, wherein the reaction partners are mixed at a temperature of 0 ° C to 5 ° C and allowed to react at a temperature up to room temperature.