DE2422718C3 - S-alkoxycarbonylaminomethyl-sacylamino-2,4,6-triiodo-benzoic acids, processes for their preparation and X-ray contrast media containing them - Google Patents

Description

The present invention relates to the S-alkoxycarbonylaminomethyl-S-acylamino ^ ao-triiodo-benzoic acids of the general formula 1

COOH

R ₁ -CO-NH I CH ₁ -NH-CO-O-

R,

wherein R _{1 is} either a monovalent alkyl radical with I - 4 carbon atoms, a hydroxyalkyl. Dihydroxyalkyl or alkoxyalkyl radical with 2-3 carbon atoms or a divalent alkylene radical with 2 to 6 carbon atoms [= - (CHj) ₂ _ "-] or a corresponding mono-. Di-, tri- or tetra-oxaalkylene radical, η the number 1 when R _{1 is} monovalent, and the number 2 when Fl _{1 is} divalent, and R _{2 is} alkyl, hydroxyalkyl or alkoxyalkyl, each with 1 to 3 C atoms means, as well as their physiologically well-tolerated alkali. Alkaline earth and alkanolamine salts.

The invention also relates to the method for their production and X-ray contrast media that use them Connections included.

The alkoxycarbonylaminomethyl group:

R ₁ [- O - CO - NH - CH, -]

forms the characteristic feature of the present novel contrast compounds of general formula 1. Compounds with urethane (carbamate) groups are so far in X-ray contrast media !! not been used. It was feared that urethanes are not stable enough to hydrolytic influences and, for example, heat sterilization in aqueous solution would not tolerate. It has now been found that the compounds of general formula 1 are surprisingly stable. Your aqueous solutions can be sterilized, and about the same time in Ester functions present in the molecule and even easily cleavable ether functions can be hydrolyzed without this the urethane group is affected (see process description and exemplary embodiments nos. 4, 8, 11, 12, 13, 14 and pages 18/19).

The new compounds are usually very light in the form of their physiologically well tolerated water-soluble, injectable alkali metal and amine salt solutions used, which contain about 45 50 mg J / ml.

Possible alkali metal salts are: the sodium salt and in a few special cases also that Lithium salt, which may contain a small amount of calcium and / or magnesium salt.

The amine salt is preferably salts of Al-

kanolamines used, for example from N-methylglucamine, N-methylxylamine (= 1-methylaminodeoxy- [D] -xylitol), 1 -Methylamine-2,3-propanedio], diethanolamine, monoethanolamine, tris (hydroxymethyl) -aPiinornethan.

Mixtures of the salts mentioned can also be used.

The monovalent 3 - alkoxycarbonylaminomethyl-5 - acylamino - 2,4,6 - triiodo - benzoic acids according to the general formula 11

R ₁ -CONH

CH ₂ -NH-CO-OR ₁

wherein R _{1 is} a C ₁ C ₄ alkyl, hydroxyalkyl. Dihydroxyalkyl or alkoxyalkyl with 2 to 3 carbon atoms and R _{2 has} the meaning defined in formula I, or their physiologically well-tolerated salt solutions are X-ray contrast media, which are particularly suitable for vascular imaging (vasography) and urography.

They are characterized in particular by their extraordinarily good, the best common uro / Vasographic agents usually superior, tolerability and their excellent urinary wedge, which a high concentration and thus an optimal shadow density in the excretory organs generated, but only minimally burdened the organism due to the high rate of excretion.

The compounds of the general formula I. which have a divalent alkylene radical R ₁ , namely the bis- (3-carboxy-5-acylamino-2,4,6-triiodobenzylaminocarbonyloxy) alkanes, can be represented more clearly by the general formula III

COOH

(III)

R ₁ -CO-NH I CIIrNH (Ό O Alkyleii O CO NH CH ₁ j NH-CO-R,

.1 .1

wherein R has the meaning defined in general formula I and alkylene is a divalent one

Alkylene radical with 2 to 6 carbon atoms
[= - (CH ₂ I _2. ,, -]

or a corresponding mono-, di-. Tri- or tetra-oxa-alkylene radical means.

The compounds of general Foimel III will be after intravenous administration, concentrated predominantly in and via the biliary organs eliminated. Only a relatively small proportion is quickly eliminated via the urinary organs. This Due to this pronounced organotropism, compounds are capable of dense, well-differentiated and long-lasting x-ray shadows of the gallbladder · and at the same time exceptionally good images to deliver the Gdllengänge.

In spite of this, these compounds are far better tolerated than all those that can be administered intravenously in use today Biliary contrast agent. The best compounds achieve a similarly high level of tolerability like the best uro / vasography agents in use today, which are already very well tolerated.

This is very unusual, since high biliary tract regularly results in a loss of tolerance must be bought.

For the reasons given, the compounds of general formula III or their are physiological well-tolerated aqueous saline solutions As a cholecysto- and cholangiography agent ideally suited and the existing agents as a rule think. Some representatives of it are also used as vasographic agents due to their optimal tolerance usable, for example the compounds E, F and especially G. which are opposite to the Vasography means, which about a connection; the general formula II contain, additionally still by a lower osmotic pressure with identical Mark iodine concentration mg iodine / ml.

The following tables show the essential pharmacological properties of the shading 3 - alkoxycarbonylaminomethyl - 5 - acylamino-2,4,6-triiodo-benzoic acids and the best X-ray contrast media in use today.

The data were determined in all cases using identical methods and under the same conditions. They are therefore directly quantitatively comparable with one another.

It means
1 = .l-methoxycarbonylaminomethyl-S-acelylamino-

2,4,6-triiodobenzoic acid (Example 1),
2- .VMelhoxycarbonylaminomethyl-S-propionyl-

amino-2,4,6-triiodobenzoic acid (Example 2).
3 = 3-methoxycarbonylamino-methyl-5-hydroxy-

acetylamino-2,4,6-triiodo-benzoic acid (Example 4). 4 = .V ETHoxycarbonylaminomethyl-S-hydroxy-

acetylamino-ZAii-triiodo-benzocic acid (Example 8). 5 ^: - 3-ethoxycarbonylaminomethyl-5-methoxy-

acctylamino-2,4,6-iriiodo-benzocic acid (Example 9). 6-- ^: 3- ( _/ i'-Hydroxyalhoxycarbonyl) aminomethyl-5-acelylamino-2.4.6-iriiodo-benzoic acid

I example II).
7 --- 3 - (,; - Hydroxyethoxycarbonyl) -aminomethyl-

5-h> droxyacet.vlamino-2.4.ft-lriiodide-benzoe-

acid (Example 13).

X ^; 3 - (^ Mclhoxyälhoxycarboiiyl) -aminomethyl-5-acelylamino-2.4.fi-lroiodobenzene / .oic acid
(Example 17).

9 = 3 - (/ j-Methoxyethox \ carbonyI) -arninorneth \ ⁱ l-5-methoxyacelylamino-2,4,6-triiodo-benzoic acid
(Example IXc).

K) = 3,5-bis (aceiylamino) -2,4,6-triiodo-benzoic acid
(Non-proprietary name [international non-proprietary name INN] = AM1DOTR17OAT) CH-PS 3 32 64 ^ and 3 37 613).

11 = 3-acetylaminomethyl-5-aceiylarnino-2.4.6-tri-

iodo-beiizoic acid (INN = IODAMiDl (CH-P. ¹ : 4 14 063).

12 = 5-Acetvlamino-2.4.6-triiodo-N-methylisophthal-

amidsä'urellNN = AClDUM lOTÄLAMICUM (CH-PS 4 24 751).

Table 1

Compounds of the general formula II

connection 1 I. 'nvi / INIl I) L _{,; i} . intr.! \ cnös Elimination in "u de
1st v. Can of lon
KK) mg ki: on the rabbit
after ί Sld. urine rniiS kt! | iniiiJ kj.'l bile SX 3 3,200 7 SOO 4th X 5 4th 1 900 6 900 3 93 5 3,300 7 700 5 80 6th 3 450 7 600 7th 83 7th 2 470 6 900 4th S. 2,400 7,000 74 9 2,500 6 9 (M) Il 97 IO 3,200 7,300 73 I! 3,200 7,000 K) 71 2 6,800 83 7 050 80 6,300 Explanation

The compounds arrived in the form of their aqueous N-methylglucamine (MGA) salt solutions Administration.

toxicity

White male mice were used for this purpose. Dose information is based on acid (S) and iodine (I).

Urinary and biliary excretion

Anesthetized rabbits were catheterized the ureter or the bile duct urine and bile continuously intercepted. In these secretions the content of the administered iodinated compounds was determined by determining the iodine content determined by an Autoamilyzer. The excretion rate and rate became the measurement values calculated.

results

From Table I it can be clearly seen that the monovalent 3 - Alkowcaibonv kiminomclhyl - 5 -acvlamino-2.4.6-triiodo-benzocic acids No. I to 9 1111 generally have very excellent intravenous tolerability and at the same time a maximum urine excretion and -uuotc.

You can easily reach the corresponding level B -der best in practice, modern urography agents No. H), 11 and 12.

The compounds No. 1, 3, 4 and 8 exceed C -. Even the already quite excellent compatibility of these proven agents. I) =

The urinary excretion rates of the new urethane derivatives No. 1 to 9 (mean value E - = 84%) usually surpass the best known urogiaphy milk nos. 10.11 and 12 (MiHeI value = 78%). F =

After all, the simplest connection no. 1 already surpasses all comparable known connections both in terms of tolerability and G = urine excretion.

The bis (3-carboxy-5-acylamino-2,4,6-triiodo-benzyIaminocarbonyloxy) alkanes listed below H =

Compounds A through G are compared with the best intravenous biliary contrast media in use today H and I and with the one in the clinic immediately before 20 1 = the introduction to the practice also well-proven connection K compared: Table 2. "K =

It means

A = 1.2-bis (3-carboxy-5-acetylamino-2,4,6-triiodobenzylaminocarbonyloxy) ethane (Example 19).

1.3-bis- (3-carboxy-5-acelylamino-2.4.6-triiodobenzylaminocarbonyloxy (-propane (example 20).

1.4-bis (3-carboxy-5-acetylaniino-2,4,6-triiodobenzylaminocarbonyloxy) butane (Example 21).

benzylaminocarbonyloxy) hexane (Example 22).

1,5-bis- (3-carboxy-5-acetylamino-2,4,6-triiodobenzylaminocarbonyloxy) -3-oxa-pentane (Example 23),

1,8-bis (3-carboxy-5-acetylamino-2,4,6-triiodobenzylaminocarbonyloxy) -3,6-dioxa-octane (Example 24).

1,2-bis- (3-carboxy-5-hydroxyacetylamino-2,4,6-triiodobenzylamino-carbonyloxyH'ithane (Example 25).

Adipinoyl-bis- (3-carboxy-2.4,6-triiodo-anilide)

(INN ^ aDIPIODON [E]. Lodipamide) (U.S. Patent 2,776,241).

Diglycoloyl-bis- (3-earboxy-2,4,6-triiodo-anilide) (INN = ACIDUM IOGLACAMICUM) (US-PS 27 76 241),

4.7.10.1 S-Tclraoxahexadecane-l.l 6-dioyl-bis- (3-carboxy-2,4.6-triiodo-anilide) (INN = ACIDUM IODOXAMICUM) (U.S. Patent 3,654,272).

Table 2

Compounds of the general formula III

Ver
am
manure Tn \ i-
quote
π u "
niu'ktt
Mouse,
i ν excretion
in% of iv devotion
from HKl mg; kg
Rabbit (3 hrs 19th O 2.9 CholczYslographic
11 dog 2) cat
Dose: HK) mg acid kg as Mt
Hoppe indices by hours 1 2 1 : iA-Sal / b S. Choliingioeraphy
Rating by hour
(see explanations! 1 T en 4th Bile urine 21 2.6 1
0 1
0.5 1
0.5 4th 1
2.5 1.5 1 : 1
1
1 0
1.5 0
1 Λ 8100 5 (1 12th 5.5 1)
2) 1 1.5 3.3
2.5 1.5
Ί 3
2.8 2.5
2.8 I.
0.5 3
3.3 4th
2.5 B. 7400 54 7th 11th 1)
2) 1.8
1.3 2
2.3 2.3
2.3 3
2.8 2.5
2.5 2.5
2.5 3
3.3 3.3
2.5 1 1 C. 3950 66 13th 4.6 1)
2) 0.8
1 1.5
2.3 2
2.5 3
3 1.8
2.5 1.8
2.5 3
2.8 1
2.5 0.5
2.3 0
0 D. 3700 78 19th 3.2 1)
2) i.5
1 2.3
1.8 2.5
2.3 2
2.5 2.5
2.5 2.5
2.5 2.3
2.5 2.8
3 3 T E. 10500 60 13th 5.8 D.
2) 0.5 1.5 2.3 2.5
2.8 2.8 2.5 3
3 2.8 4th 4th F. 10200 60 38 1 2) 0.25 1 2 2.5 2.8 2.8 1 1 1.5 1.5 G 12270 76 41 0.7 2) 0.9 1.4 1.8 2.5 1.8 0.5 0.9 H 2400 38 17th 4.6 D. 0.8 1.3
0.5 1.7
0.7 2.3 1.9 2.5 2.3 0.75 0.5 0.3 1 3750 30th 1)
2) 1.8 2.6 2.8 1.8
1.2 2.7 1.5 O.S. O.S. K 4850 77 1) 2.8 2.4

20th

Explanations

Toxicity and biliary urinary excretion were determined according to the methods explained in Table 1. Bile / urine = Q.

Cholecystographic effect

Evaluation of shadow density and quality of the contrast image:

0 = negative.

1 = weak,

2 = sufficient.

3 = good.

4 = excellent.

15th

(J. O. Hoppe: J. Amer. Pharm. Assoc. Sci. Ed. 48 .. pp. 368 to 379 [1959].)

Cholangiographic effect evaluation according to the following standard:

no shadow.

Gallbladder duct (duetus cysticus) visible.

The duct of the liver (duetus cholcdochus) is visible.

Liver duct (duetus hepaticus) visible.

intrahepatic bile ducts (duetus biliferi) visible

results

The compatibility of the bis (3-carboxy-5-acylamino-2,4,6-triiodo-benzylaminocarbonyloxy) - alkanes A. B. C, D. E. F and G is 2 to 5 times larger than that of compound H. the most frequently used so far intravenous bile contrast medium.

Compounds ABE F and G are I ¹ , - to 2 ¹ Z ₂ ITIaI better tolerated than the most well-tolerated previously known biliary contrast media I and K. The biitropism expressed in the gall, urinary quotient Q - is in the compounds ABC D, E. F and G. generally also more pronounced than with the established compounds H. I and K: average values for Q 5.1 and 2.1, respectively. The new connection (B) with the weakest quotient even exceeds the average value of the established connections. The gall bladder and bile ducts of the test animals are also better mapped with the new connections than with the tried and tested means.

The use of iodized organic compounds as X-ray contrast media has long been common: see R. B a r k e. X-ray contrast media, Georg Thieme Leipzig 1970; P. K. Knoefel, Radiocontrast »gents. International Encyclopedia of Pharmacology »Nd Therapeutics, Pergamon Press Oxford 1971. Nevertheless, even the newer contrast media still many wishes open. In particular, a further increase in tolerability is both in the Uro / vasography agents as well as intravenous cholecystography agents are particularly desirable. Maximum urine excretion is also necessary for uro-vasography agents. The sum of the urine and bile excretion should reach about 90% after 3 hours, which means long-term damage could be excluded a priori by the contrast agent.

In the case of intravenous biliary contrast media, it is necessary to have a high level of tolerance and gallability at the same time to reach. In other words, properties that are usually mutually exclusive.

With the present invention, as shown, these wishes largely satisfied.

The process of making the as an indicative Components in X-ray contrast media !! and as intermediate door X-ray contrast media usable 3-alkoxycarbonylaminomethylö-acylamino - 2.4.6 - triiodo - benzoic acids and their sal / .e is characterized in that one is known per se A 3-ainomethyl - 5 - amino - or 5 - nitrobenzoic acid derivative in any order of alicemy formula IV

X "

COOH
1 X,

(IV

CH, -N H,

wherein A is an amino or nitro group and X _:. X ₄ and Xf, .iodo-. Mean chlorine or hydrogen atoms. with a reactive carbonic acid ester of the general formula V

R ₁ "- [O - CO - Y] ,,

wherein Y is chlorine. Bromine. Iodine atom or an aryloxy radical, R ₁ "is an alkyl radical with 1-4 carbon atoms, a hydroxyalkyl or dihydroxyalkyl radical with 2 to 3 carbon atoms, the hydroxyl groups of which are usually obtained by esterification, an easily cleavable ether function

■ 5 or masked by acetal or ketal functions, an alkoxyalkyl radical with 2 to 3 carbon atoms or a divalent alkylene radical with 2 to 6 carbon atoms or a corresponding mono-, di- or poly-oxaalkylene radical and η the number 1. if Ri "is univalent.

and the number 2. when R ₁ "is divalent. Or with phosgene and an alcohol R ₁ " - OH / u an N- (3-carboxybenzyl urethane of the general formula VI

COOH

CH, -NH-CO-O -R ₁ '

implements, if necessary A and X ₂ . X ₄ and / or X "are converted into an amino group or into hydrogen by reduction and the aromatic nucleus is triiodinated. unc the aromatic amino group acylated by reaction with an acid of the general formula VI.

R, "- COOH

(VIII

where R ₂ "is an alkyl or a hydroxyalkyl radical with 1 to 3 carbon atoms, whose hydroxyl group is masked by esterification or an easily cleavable ether function or an alkoxyalkyl radical with 1 to 3 carbon atoms, and with dehydrating agents or with an anhydride or Chloride this acid.

The reactive carbonic acid ester of the formula V came to a corresponding carbonic acid-half-ester-halo

gen id or a mixed carbonic acid ester with an aliphatic alkoxyl group R ₁ "- O - and an aromatic aryloxy group. For example a phenoxy, tolyloxy or nitrophenoxy group.

The preferred method practice is in that 3-Aininomethvl-5-amino-2,4,6-triiodo-benzoic acid is used as the starting material and a carbonic acid half-ester chloride (= chloroformic acid ester) is used as the carbonic acid ester of the formula V, which is used with it obtained N- (3-carboxy-5-amino-2,4,6-triiodo-benzyl) urethane then acylated on the aromatic nitrogen and finally the desired N- (3-carboxy-5-acy! amino-2,4,6-triiodo-benzyl) urethane isolated, at the same time any protecting groups, which Mask hydroxyl functions, split off hydrolytically , preferably by gentle heating in an alkaline medium.

The order of the conversions according to the method of the invention can also be rearranged in that way be that the urethane group is introduced at an earlier stage of the synthesis, by already having an intermediate product in the synthesis of 3 - aminomethyl - 5 - amino - 2,4,6 - triiodo - benzoic acid, which, however, must already have a preformed 3- / minomethyl group. with a reactive carbonic acid ester, preferably with a carbonic acid half-ester chloride. implements and the received Product according to methods known per se into the corresponding 3-alkoxycarbonylaminomethyl-5-amino-2,4,6-triiodo-benzoic acid convicted.

As suitable intermediates in the synthesis of 3 - aminomethyl - 5 - amino - 2,4,6 - triiodo - benzoic acid come into consideration 3-aminomethyl-5-aminobenzoic acid, 3-aminomethyl-5-nitro-benzoic acid or a 2,4- or 6-mono- or dihalogen derivative thereof: E. F e 1 d er et al., Helvetica chimica Acta 48: 259-274 (1964). See example 10a.

In this case, you may have to use the reaction product reduce with the carbonic acid half-ester chloride, whereby the 5-nitro group into the 5-amino group transferred and possibly existing haloene atoms are replaced by hydrogen, and then triiodine the reaction product obtained. For example, through conversion with iodine chloride or an alkali iodine dichloride: Example 10b.

The reaction with the chloramic acid ester is usually in aqueous solution or with Water-miscible solvent and carried out at a temperature range from about 0 to about 40 C.

As mentioned on ropes 13 and 15, the hydroxyl functions in the radicals R ₁ "- and R" are usually reversibly masked by esterification, an easily cleavable ether function or, in the case of dihydroxy compounds, by an acetal or ketal function. This is sometimes necessary in order to rule out undesired side reactions of the hydroxy function.

In addition, the following are suitable: as ester groups, preferably lower acyloxy groups. Halogen functions Chlorine, bromine or iodine (= hydrohalic acid ester); as an easily split ether group: benzyl, Diphenylmethyl, triphenylmethyl (= trityl) or trimethylsilyl ether groups: as acetal or ketal groups: Acetals with formaldehyde, acetaldehyde or benzaldehyde or ketals such as acetone.

These protective groups can usually be removed after acylations with anhydrides during work-up Anyhow necessary slight heating in an alkaline solution, by acid hydrolysis or easily split again by transesterification (Example 11c). Usually, no particular stage of reaction is required for this.

Compounds of the general formula I. which have an alkoxyalkoxycarbonylaminomethyl or an alkoxyacylamino group have, can also from corresponding haloalkoxycarbonylaminomethyl or haloacylamino compounds can be obtained by reaction with an alcohol.

X-ray contrast media according to the present invention contain, for example, at least one dei the following compounds of general formula 1 or their physiologically well-tolerated salts:

1. General formula 1. if 11 =

I. -CH, -CH, CH, - OH -CH, -CH, 2 -CH, -CH ₄ -CH, -CH, -OH 3 -CH, -CH, CH, -CH, - O - CH, 3a -CH, -CH, CH, -CH, 3b -CH, -CH ₁ - -CH, -CH, 3 c -CH, -CH ₂ - -CH, -OH 4th -CH, -CH, - -CH, - O - CH, 5 -CH, -CH, 6th -CH, -CH, OH 7th -CH, CH, -CH, 7a -CH, CH, 7b -CH, CH * 7c -CH, - CH, 8th -CH, -CH ₃ OH 8a -CH, -CH, - O - CH, 9 -CH, -OH -CH ₂ -OH - OH = (CH ₂ OH), -CH (OH) - -CH, - -CH ₂ - -CH ₂ - -0- -O- -O-

13th

2. General formula 1. if η = 14

A - CH ₂ - CH ₂ -

G - CH ₂ - CH ₂ -

B - CH ₂ - CH ₂ - CH ₂ -

C - CH ₂ - CH ₂ - CH ₂ - CH ₂ -

D - (CH ₂ V, -

E -CH ₂ CH ₂ -O-CH ₂ -CH ₂

E ₁ - CH ₂ CH ₂ - O - CH ₂ - CH ₂

E ₂ - CH ₂ CH ₂ - O - CH ₂ - CH ₂

E, - CH ₂ CH ₂ - O - CH ₂ - CH ₂

F / L - (CH ₂ CH ₂ O) ₂ CH ₂ CH ₂ -

M / N - (CH ₂ CH ₂ O) ₃ CH ₂ CH ₂ -

O / P - (CH ₂ CH ₂ Ol ₄ CH ₂ CH ₂ -

Q / R / S - (CH ₂ CH ₂ O) ₂ ^ ₄ CH ₂ CH ₂ -

CH,

CH, - OH

CH,

CH,

CH,

CH,

C ₂ H ₅

CH ₂ - OH

CH ₂ O - CH,

CH, or - CH ₂ OH

CH, or - CH ₂ OH

(H, or CH ₂ OH

CH ₂ - O - CH,

stability

The compounds of general formula 1 were found to be surprisingly stable.

Your aqueous salt solutions, which are used as X-ray contrast media are used can be heat-sterilized without difficulty.

Quantitative studies have shown that when aqueous solutions of compounds of the formula 1 are heated at 120 ° C. for 150 minutes, as a rule no or only minimal hydrolysis of the R ₁ O-CO-NH-CH ₂ - occurs, while under the same conditions corresponding urea derivatives the ureido group

R —NH — CO —NH CH ₂ - to K) is hydrolyzed to 15%.

The Hydroxyalkoxycarbonylaminomclhy! Compounds Table 3 Nos. 3 and 4 are even considerably more stable than comparable ones under the same conditions / i-Hydroxyäthyl - amide with classic Structure Table 3, No. 5.

Table 3

COOH

A - NHCH, I NHCO-B
.1

Kr. connection A. 1 CH ₃ -CH ₂ -O-CO- 2 (CHO ₂ CH-O-CO- 3 HO - CH ₂ CH ₂ - O - CO - 4th H OCH ₂ CH ₂ CH ₂ - O - CO - OH 5 CH ₃ CO - 6th H ₂ N-CO- 7th CH ₃ NH- CO -

-CH, stable -CH, stable -CH, 0.5% -CH, 0.7% -CH ₂ CH ₂ -OH 10% *) -CH, 3 5% -CH, 2%

Hydrolysis of the Λ - NH-Hunklion after Heating of saline solutions

30 min / 120 C 150 min / 120 C

stable stable 1%

- 30% *) 12 -15% 10%

• 1 llMlmlw lld NH CO B-liinMion / u \ H,

Process and substance examples
A. Tri-iodine compounds: General formula I.; i = 1

B e i s ρ i e i 1

3 - Melhoxyearbonylaminomethyl - 5 - acetylamino-2,4,6-iriiodobenzoic acid = N-O-acetylaminoo-carboxy - 2,4,6 - triiodobenzyl) - carbamic acid methyl ester

General formula: R ₁ = R ₂ = methyl, / i = i

a) 3-MethoxycarbonyIaminomethyl-5-amino-2,4,6-triiodo-benzoic acid

K) Og 3-aminomethyl-amino-2,4,6-triiodo-benzoic acid (0.184 mol) - E. F e 1 d e r et al., Helvetica chimica Acta 48.259 (1965), Swiss patent

4 15 668 - are suspended in 750 ml) of water and brought into solution by adding 184 ml of 1N aqueous sodium hydroxide solution.

A solution of 18.5 ml of methyl chloroformate (0.24 Mol) in 50 ml of acetone and 1N sodium hydroxide solution (184 ml) were added dropwise with stirring over the course of 12 hours, whereby the pH of the solution is kept between 10.5 and 11.

The reaction solution is filtered clear and diluted in Stir in hydrochloric acid. The precipitated crude product is filtered off. washed with water and brought into solution by adding a little sodium hydrogen carbonate. By adding saturated Saline solution is the sodium salt of 3-methoxycarbonylaminomethyl-5-amino-2,4,4-triiodobenzoic acid crystallized out. The precipitate is filtered off, dissolved in water, and added the free acid is removed from dilute hydrochloric acid.

40

45

Yield: 89.5 g (81.3% of theory).
Melting point: 121 122 C.

C ₁₀ H ₉ J ₃ N ₂ O ₄ :
3c calculates ..
found ..

C 19.95. J 63.25 "
C 19.74. J 63.80 "

Equivalent weight:
Calculated ... 601.9:
found ... 601.

Thin layer chromatogram (TLC) on silica gel with butanol / glacial acetic acid / water = 3: 1: 2. R ₁ = 0.50. "

b) 3-Methoxycarbonylaininomet! ivl-5-acetylamino-2,4,6-triiodobenzoic acid

18 g of 3-melhoxy-carbonylaminomethyl-5-amino-2,4,6-triiodobenzoic acid (0.03 mol) in 40 ml of glacial acetic acid and 10 ml of acetic anhydride are added after addition heated by 0.1 ml of sulfuric acid on the steam bath for 4 hours.

After positions over after! the resulting precipitate is sucked off. washed with water and purified hydrochloric acid by falling over with sodium hydroxide solution.

Yield: 16.9 g (87% of theory).

Melting point: 175 IHO C.

C ₁₂ H ₁ , .1, N ₂ O ₅ :

Calculated . . . C 22.3S. .1 59.12 ",,:
L'Found ... C 22.06. .1 54.57 ",,.

Equivalent weight:
Calculated ... 643.94.
found .. . 642.

TLC on silica with butanol glacial acetic acid; Water = 3: 1: 2. Rf = 0.48.
Solubilities:

Slightly soluble in water, methanol and chlorine form, slightly soluble in hot ethanol.
Na and N-methyl glucamine salt: easily soluble in water.

The free acid takes 1 crystal water in moist air and forms a hydrate.

Example 2

3-methoxycarbonyl: iminomethyl-5-propionyIamino-2,4,6-triiodobenzoic acid

R, = - CH ₃ . R ₂ = C ₂ H ₅ . / 1 = 1

22.5 g of 3-MethoxycarbüπylaminoInethyl-5-amino-2,4,6-triiodobenzoic acid (0.0374 moles) becomes 45 in! Propionic acid i-.ihydnd with 3-4 drops more concentrated Sulfuric acid is added and the mixture is heated on the steam bath for 26 hours while stirring.

The excess propionic anhydride is evaporated off in vacuo and the residue is treated with Water. The crude product is dissolved in dilute sodium hydroxide solution and the solution at pH 10 10.5 during Heated to 50 ° C. for 40 minutes. The product is precipitated by adding dilute hydrochloric acid and purified over the ammonium salt.

Yield: 22 g (90% of theory) "dC: R ₁ - 0.5.

Melting point: 166 167 C.

C ₁₃ H ₁₃ J ₃ N ₂ O ₅ :
Calculated
found

Solubilities:

Insoluble in water. Benzene. Chloroform and ethyl acetate, easily soluble in methanol and Ethanol.

Sodium (Na) salt: 50 g / KK) ml water at 20 C.

N-methylglucamine <MGA) salt:> 100 g 100 ml water at 20 ^° C.

Example 3

3 - Melhoxyearbonylaminomethyl - 5 - butyryiamino-

2.4,6-triiodo benzoic acid
R, = - CH ₃ . R ₂ = C ₃ H ₇ . / i - I

Production analogous to Example 2 using of bulric anhydride.

Melting point: 165 166 CDC: R ₁ = 0.53.

C ₁₄ H ₁₅ J ₃ N ₂ O ₅ :

Calculated ... C 25.02. J 56.65%:
found ... C 25.27. .1 56.75%.

Soluble wedges:

Insoluble in water. Benzene and chloroform, easily soluble in methanol.

H c 1 s ρ 1 e 1 4

3 - MethoxN "carbonv lamiriomelhv I - 5 · incirowaceU I-amino-2.4.f) -triiodobenzoic acid

C 23.73. .1 57.86 "!":
C 23.73. .1 5 ".9S ⁰ O.

R,

C ^- H ₁ . R,

cn, on.

/ u 22.5 μ 3-Meilio \ vairbon \ lammomeilu 1-5-amino-2.4.6-iriiodobenzoic acid (0.037 minor in ^l ) 0 nil di-

/ IO

methylacetamide are at 0 C within - 20 minutes 10.9 g of acetoxyacetic acid chloride (0.08 mol) were added dropwise. The mixture is stirred for a further 15 hours at R.i. and then stir the reaction mixture in 250 ml of water one. The precipitated product is suspended in 150 ml of water, heated to 50 OC and washed with 1N sodium hydroxide solution brought to pH 9.5 and additional sodium hydroxide salt kept at this pH level, converting the 5-acetoxyacetylamino group into the 5-hydroxyacetylamino group is hydrolyzed. The reaction solution is decolorized with activated charcoal and diluted in Hydrochloric acid added dropwise, whereupon the desired end product precipitates.

Yield: 21.7 g (88.3% of theory).

Melting point: 96-199 CDC: R ₁ = 0.405.

C ₁₂ H _n J ₃ N ₂ O ₁₁ :
Calculate! ..
found .

C 2 !, 84, J 57.68%:
C 21.67,.! 57.65%.

Equivalent weight:
Calculated ... 659.94,
found ... 661.

Solubilities

25 C Boiling temperature water 0.7% 8th% Methanol 5% 45% Ethanol 4% 10% Na-SaIz > 100% MGA SaIz 60%

30th

35

This acid can be recrystallized from water.

Example 5

3 - methoxycarbonylaminomethyl - 5 - methoxyacctylamino-2,4,6-tr; iodine benzoic acid

40

R ₁ =

CH ₃ , R ₂ = - CH ₂ - O - CH ₁ . / ι =

24 g of 3 - methoxycarbonylaminomelhyl - 5 - amino-2,4,6-iriiodo-benzoic acid (0.04 mol) are dissolved in 60 ml of dimethylformamide. Distilled from the solution remove about 20 ml of solvent to completely eliminate the moisture: Solution 1. In a second Reaction vessel contains 9 g of methoxyacetic acid (0.1 mol) in 50 ml of dimethylformamide at 2 3 C in 25 minutes, 11.9 g of thionyl chloride (0.1 mol) were added dropwise. After a further 30 minutes this solution becomes prepared solution I and added for 15 hours stirred at room temperature. The starting material is gradually disappearing: detection by means of Thin layer chromatography. The reaction mixture is then poured into 400 ml of water.

Yield: 25.8 g ^ (92%).

Melting point: * 245 CDC: R ₁ = ■ 0.46.

Microanalysis after purification via the cyclohexylammonium salt:

C ₁₃ H ₁₃ J ₃ N ₂ O ,,:

Calculated ... C 23.16. .156.48%:

found ... C 23.29. .1 58.49 "· ,,.

Na- and MGA-SaI / very easily soluble in water

Example 6

3- ^ thoxycarbonylamimimethy! -5-acet \ lamino-2,4,6-triiodo-benzoic acid

R ₁ = C ₂ H ₅ . R ₂ = - CH.,. η - 1

a) 3-Ethoxycarbonylaminomethyl-5-amino-2.4.6-iri-

iodo-benzoic acid

218 «3-aminomethyl-5-amino-2.4.6-triiodo-benzoic acid (0 4 mol) in 1500 ml of water and 400 ml of 1N sodium hydroxide solution are at room temperature and pH 10 to 1 «simultaneously dropwise with a solution 43.2» ethyl chloroformate (0.4 mol) in 1M) ml of acetone and 400 ml of 1 N sodium hydroxide solution are added. The mixture is stirred for a further 1 hour, adjusted to pH 7 and then extracted the reaction solution with ethyl acetate and chloroform. The aqueous layer is evacuated freed from adhering solvent and in 1100ml diluted hydrochloric acid stirred in. The crude product is dissolved in 200 ml of water and 40 ml of 10 N sodium hydroxide solution uelöst. The sodium salt is made by adding table salt salted out and similar to that described in the example lai worked up.

Yield: 201 g (83% of theory).

Melting point: 225 C decompose. D.C .: R, = 0.60.

C ₁₁ H ₁₁ J ₃ N ₂ O ₄ :

Calculated ... C 21.45. J 61.81%: found ... C 21.32. .161.70%.

b) 3 - ethoxycarbonylaminomethyl - 5 - acetylamino-

2.4.6-triiodo-benzoic acid c

Control analogous to Example I b).

Yield: * 73% of theory.

Melting point: 150 155 CDC: R ₁ = 0.54.

C _n H _n J ₃ N ₂ O ₅ :

Calculate. . C 23.73. J 57.86%: found. C 23.52. .1 57.65%. Solubilities:

Slightly soluble in water and chloroform, slightly

soluble in methanol and ethanol.

Na and MGA salts:> 100 g 100 ml water 20 C.

Example 7 General Formula 1

a) R ₁ = - C ₂ H ₅ . R ₂ = - C ₂ H ₅ . η - I

Production: analogous to example 2.

Yield: 90% of theory.

Melting point: 233 235 CDC: R ₁ = 0.57.

C _U H _1S .I ₃ N ₂ O ₅ :

Calculated ... C 25.02, J 56.65%: found ... C 24.90: .1 56.62%.

Slightly soluble in water and chloroform, slightly soluble in methanol.

b) R ₁ - - CAU. R, = ■ ■ C ₁ H-. 11 - I.

Production: analogous to example 2 3.

Yield: 73 "0.

Melting point: 146 147 CDC: R ₁ 0.66.

Calculated ... C 26.86. J 55.5O ¹ O: found. .. C 26.36. J 55.3S ",,.

Slightly soluble in water and chloroform, slightly soluble in methanol. Absorbs 1 mol of crystal water in moist air.

Example 8

3 - Ethoxycarbonylarninomethyl - 5 - hydroxyacelylamino-2,4,6-triiodobenzoic acid

R ₁ = - C ₂ H ₅ , R ₂ = - CH ₂ - OH, "= 1

24.8 g of 3-ethoxycarbonylaminomethyl-5-amino- ίο 2.4,6-triiodo-benzoic acid, dissolved in 50 ml of dimethylacetamide, are mixed with 13.6 g of acetoxyacetyl chloride (0.1 mol) were added and the mixture was stirred at room temperature for 18 hours. Now the reaction mixture is in Stir in 400 ml of ice water. The 5-acetoxyacetylamine O 'compound formed Grooves. It is sucked off, washed with a little water and diluted in Sodium hydroxide solution dissolved. The solution is heated to 60 C and diluted by adding Sodium hydroxide solution kept at pH 10, with the acetoxy group is saponified. After the sodium hydroxide consumption has ended, 18% hydrochloric acid is used acidified. The 5-hydroxyacetyl compound precipitates.

Yield: 25 g (93% of theory).

Melting point: 140-145 "C. D.C .: R, = 0.48.

C ₁₃ H ₁₃ JjN ₂ O ₁₁ :

Calculated ... C 23.17, J 56.49%;

found ... C 22.99, J 56.00%.

Absorbs 1 mol of crystal water in moist air. Solubilities:

Soluble in boiling water, in methanol and ethanol, slightly soluble in cold water and Chloroform.

Na and MGA salt: easily soluble in water.

Example 9

3 - Ethoxycarbonylaminomethyl - 5 - methoxyaeetylamino-2,4,6-triiodo-benzoic acid c

R ₁ = - C ₂ H ₅ , R ₂ = - CH ₂ - O - CH ₃ , η =

To 9 g of methoxyacetic acid (0.1 mol), dissolved in 50 ml of dimethylformamide, are added in 15 minutes 11.9 g of thionyl chloride (0.1 mol) were added dropwise while cooling with ice water. The solution will be another 1/2 hour stirred at room temperature and then with 24.8 g of 3 - ethoxycarbonylaminomethyl - 5 - amino - 2.4,6 - triiodo-benzoic acid (0.04 mol) added. The reaction mixture is now lurbinated for about 12 hours then stirred into 300 ml of water. After a few hours, the resulting precipitate is suctioned off, washed with cold water and transferred from dilute sodium hydroxide solution with hydrochloric acid.

Yield: 21.2 g (76% of theory).

Melting point: ^ 228 CDC: R ₁ = - 0.4.

CuH ₁₅ J ₃ N ₂ O ,,:
Calculated
Found

Solubilities:

Slightly soluble in water and chloroform, soluble in boiling methanol and ethanol.
Na and MGA salts: easily soluble in water.

Example K)

3 - Isopropoxycarbonylaminomelhyl - 5 - acetylamino-2.4.6-triiodo-benzoic acid

R ₁ = - CH (CH.,) ,. R ₂ = - CH 1, Ji = 1

a j 3 - isopropoxycarbonylaminomethyl - 5 - nitrobenzoic acid

17.1 g of 3-aminomethyl-5-nitro-benzoic acid (0.08 Moll in 100 ml of water, 50 ml of ethanol and 40 ml of 2N sodium hydroxide solution are cooled with ice water at the same time dropwise at pH 10 11 with a solution of 10 g of isopropyl chloroformic acid (0.08 mol) in 40 ml of acetone and 40 ml of 2N sodium hydroxide solution offset.

The reaction solution is aal 150 ml in a vacuum evaporated and acidified with hydrochloric acid. The raw product fills out. It can umkiistallisicit from ethanol will.

Yield: 19.2 g (85% of theory).

Melting point: 62 163 C.

C ₁₂ H ₁₄ N ₂ O ₁ ,:
Calculated .
Found.

C 51.06, N 9.93%;
C 51.31. N 9.96%.

hl 3 - isopropoxycarbonylaminomethyl - 5 - amino-2.4.6-triiodo-benzoic acid c

0.02 mol of the above substance 3 a) in 150 ml of water and 20 ml of 1N sodium hydroxide solution are in the presence of 0.5 g of 10% palladium-activated carbon analyzer hydrogenated at room temperature. After the calculated amount of hydrogen (1350 ml) for reduction the Nilro group is included. the catalyst is filtered off, the filtrate mil '0 (XImI water and so much dilute hydrochloric acid is added until a pH of 2 is reached.

70 ml of 1 N potassium iodine dichloride (KJCl ₂ ) are now added dropwise with thorough stirring in a room temperature, and the mixture is stirred for a further 12 hours.

The precipitated crude product is suction filtered into 30 ml of water and as little as possible 20% iycr Sodium hydroxide solution dissolved. The sodium salt is precipitated by adding saturated sodium chloride solution. This is filtered off at OC, washed with a little saturated sodium chloride solution and then poured into 200 ml Dissolved water, decolorized with activated charcoal and added dropwise to dilute hydrochloric acid, whereupon the product precipitated will.

Yield: 8.7 g (69% of theory)

Melting point: 209 210 C.

C 24.44. J 55.34%:
C 24.26. .1 55.54%.

Calculated
found

C 22.88. .1 60.44%:
C 23.03. .1 59.65%.

Ät | uivalcntgewichl:

Calculated ... 688.0.
found . . . 685.

Equivalenlgcwichl:

Calculated .. 629.99.
Found. . . 632.

c) 3 - isopropoxycarbonylaminomethyl - 5 - acL-niamino-2,4.6-t ri iodine benzoic acid

Production analogous to Example 1 b).

Yield: 62% of theory. ,

Melting point: 238-240 C.

When recrystallizing from ethanol, it becomes Knstallform changed. It now melts at 195 C.

TLC on silica gel with butyl acetate-glacial acetic acid water = 5: 1: IR _f = 0.18.

C ₁₄ H ₁₅ I ₃ N ₂ OS:

Calculated ... C 25.02. .1 56.66%:
found ... C 24.66, J 56.72%.

Equivalent gcwichl:, ^

Calculated ... 672.
found ... 671.
Soluble wedges:

Insoluble in water, soluble in boiling ethanol. Na and MGA salt: K) Og KK) ml of water from 20 C.

Example 11

3 - (/; - Hydroxyätho \ ycarbonyI) -aminometüvl-5-acct ;, iamino-2.4.6-lri iodo-benzoic acid

R, = CH ₂ CH, OH. R ₂ - C \\ _} . η ■ --- I

a) 3 - (/) - Benzyloxyethoxycarbonyl) aminometh 1-5-amino-2,4,6-triiodo-benzoic acid

In a solution of 54.3 g of 3-aminomethyl-5-amino-2,4,6-triiodo-benzoic acid (0.1 mol) in K) OmI water and KK) ml of 1 N sodium hydroxide solution are added with stirring at 10 15 C and while maintaining a pH range of 10 to 11 at the same time 21.5 g of Benz.yloxyäthoxycarbonylchlorid (= Benzyloxyethyl chloroformate) (0.1 mol) and K) OmI! N-caustic soda dripped in. The sodium hydroxide solution is used to neutralize the reaction of the hydrochloric acid released.

The reaction solution is adjusted to pH 7 and extracted with chloroform and ethyl acetate. The extract is discarded. The aqueous layer is evacuated freed from the remaining organic solvent and stirred into dilute hydrochloric acid. The precipitated crude product is obtained by reprecipitation from dilute sodium hydroxide solution with dilute hydrochloric acid cleaned. When dissolving in dilute sodium hydroxide solution, a pH of 7 is never exceeded. Before the In cases, the undissolved portion is removed.

Yield: 54.75 g (76% of theory).

Melting point: 141 C with decomposition.

TLC with butanol / glacial acetic acid / water = 3: 1: 2. R ₁ = 0.85.

C ₁₈ H ₁₇ J ₃ N ₂ O ₅ :
Calculated
found

C 29.94. .! 52.73%:
C 29.44. .1 5115%.

Equivalence weights:

Calculated . . . 722.06.
found . . . 720.

CH ₇ NHCOOCH ₁ Ch ₁ -O -CH, Ph; AcO

b) V (.; - BenzyloxyüthoxycarbonyD-aminoinL-ih \! -
5-acetvlamino-2.4.6-triiodo-benzoic acid - j

Production analogous to Example I b.t. Melting point:! 15th to 117 C.

ei 3 - (.-; - Hydroxyäthoxycarbon \ l) -aminometh \ I-5-ace'tylam'ino-2.4.6-tnjod-benzoes;! üiv

S0.6 ii 3 - (('- Benzyloxyethoxycarbon _ \! I - aminomethyl-5-amino-2.4.6-triiodo-benzoic acid in. I: Nj ₁ , h in 17 (i ml of glacial acetic acid and 25 ml of acetic acid aiiindiid are heated to 95 ° C. Heated and stirred with 1.7 ml of concentrated sulfuric acid. A clear solution is formed, which is kept at 95 ° C. for a further 24 hours and then evaporated to dryness in vacuo. The residue crystallizes on trituration with ether. it is κ dissolved veruiinnter sodium hydroxide solution and extracted with chloroform and - \\ h \ ■■ acetal extracted The aqueous layer is wills;, nd; g of organic solvents freed iduivis l:. \ akuieren ") and subsequently stirred into dilute hydrochloric acid wännge. The resulting precipitate (5K ^ μ jh _L - is composed of a mixture of 3 - (/ <'- H \ drn. \} Aiii ·. ^ ,. carbonyl) -aminometh> l-5-acetylamino-2.4. (« -ii-imdbenzoic acid (R, = 0.36) and the corresponding 3-1, -Aceioxyäthoxycarbonyl) -aminomeihv i ■ \ ererungiR, = 0.43!

!>, this mixture is in 3 (X) ml of water and 9ii ni! 1 N sodium hydroxide solution dissolved, heated to 50 C and so on diluted sodium hydroxide solution is added for a long time until the pH remains constant.

The solution is iüwicri and very carefully »Acidified. The first amorphous, parts of the 1 :: ϊΚϋΐμ are discarded. Eventually the solution will mark anäueii. whereby the desired product ausküvi.iilisicrt.

Yield: 56-65% of theory.

Melting point: 155 C sinter. 174 C / li be / i; ·! -.

TLC: R ₁ - = 0.36.

C ₁₃ H ₁₁ J ₁ N ₂ O ,,:

Calculated . .
found . .

C 23.17. J 56.49%:
C 23.00. J 56.11%.

Equivalent weight:
Calculated ... 673.97.
found . . . 679.

Solubilities:

Soluble in boiling water, easily soluble; in methanol and ethanol, slightly soluble in chloroform.

Na and MC) A salt: easily soluble in water at 20 C.

Comment:

Part of the action of excess hessetic anhydride there was an amacylation at the ^ -1 ,; - Bcnzyloxyäiho \ ycarbonyl) - amino: neih \ I group according to:

OH

CH-NHCOOCH, CH, O Ac

Ac CH, CO

O CU. Ph

Example 12

3 - (// - Hydroxyethoxycarbonyl) aminomelhy I - 5 - propionylamino-2.4.6-iriiodo-benzoic acid

R ₁ = - CH ₂ - CH ₂ - OH. R ₂ - C ₂ H ₅ . η - I

a) 3 - (// - Chlorälhoxycarbonyl) -aminometh \ l-5-amino-2,4,6-iriiodo-benzocic acid c

R ₁ = - CH, - CH, - Cl

IO

To a solution of 128 g of 3-aminomelhyl-5-amino-2.4.6-triiodo-benzoic acid (0.25 mol) in KX) O ml of water and 250 ml of 1N sodium hydroxide are added dropwise while maintaining a pH range of 10 11 a solution of 35.8 g of chloroformic acid _/ chloroethyl ester [= 1 -chloroformyl oxyallyl chloride] (0.25 mol) in 200 ml of acetone and 250 ml of 1N sodium hydroxide solution. After 30 minutes, hydrochloric acid is added up to pH 7. The organic solvent (acetone) is evaporated in vacuo. The aqueous solution is filtered and added dropwise to very dilute hydrochloric acid. The resulting precipitate is filtered off with suction. washed with water and dissolved in aqueous sodium hydrogen carbonate solution. The solution is filtered and 100 g of sodium chloride are added to the filter, whereby the sodium salt of the product is salted out. This salt is sucked off. washed with saturated sodium chloride solution, dissolved in water and decomposed by adding hydrochloric acid.

Yield: 137 g (84.5% of theory).

Melting point: 139 C sinter. 175 C decompose.

C _n H ₁₁₁ CIJ ₁ N ₂ O ₄ equivalent weight:
Calculated . .. 650.37;
found . . . 654.

D.C. with mobile solvent chloroform, methylethylcctone, Eisessiu - 10: 5: 2. R, = 0.61.

b) 3 - (/) '- Hydroxyä'thoxycarbonyl) -aminomiethyl-5-amino-2.4.6-triiodo-benzoic acid

R, - - CH, - CH, - OH

40 moniiimsalz is sucked off. Wash ge with methanol, suspended in water and brought into solution by adding 2N sodium hydroxide. The released cyclohexylamine is extracted with ethyl acetate. The aqueous layer is acidified and the product precipitates.

Yield: 14.3 g (68% of theory).

Melting point: 125 C sinter. 174 C.

C ₁₁ H _n J ₁ N ₂ O ₅ equivalent weight:
Calculated ... 631.93:
found . .. 625.

TLC with the mobile phase chloroform, methyl alcohol, glacial acetic acid = 10: 5: 2. R ₁ = 0.40.

c) - 3- |, .'-Hydroxyethoxycarbonyl) -aminornelhyl-5-propionylamino-2.4.6-triiodo-benzoic acid

12.6 g of 12b) (0.02 mol), suspended in 25 ml of Pro pionic acid canhydride. are mixed with a few drops of concentrated sulfuric acid and cooked for 2 hours heated in the steam bath. After standing overnight, the crystalline product is filtered off with suction. in diluted α Sodium hydroxide solution dissolved, heated to 50 C, by zu drop of sodium hydroxide solution kept at pH 11, danacl cooled and added dropwise to a little dilute hydrochloric acid. The product fails.

Yield: 6.7 g (49% of theory).

Melting point: 172 C sinter. 193 C decompose.

TLC with running mixture of chloroform / methyl ethyl octone glacial acetic acid = 10: 5: 2. R ₁ = 0.09.

C ₁₄ H ₁₅ JjN ₂ O ,, equivalent weight:
Calculated . . . 688:
found . . . 693.

1 oleities:

Slightly soluble in water and chloroform, see Easily soluble in methanol and hot ethanol Na and MGA salt: > H) O ti 100 ml water at 20 C.

21.5 g of 3 -, <'- chloroethoxycarbonylaminoniethyl-5-amino-2,4,6-triiodobenzoic acid (0.033 mol) are dissolved in 45 ml of water containing 8.5 g of 85 "potassium hydroxide (0.1 mol) and are dissolved overnight at 0 C. left to stand and then precipitated by dripping into excess dilute hydrochloric acid. The effect of KOH saponifies the chloritho \ y \ compound:

Cl -CHXH, -

KOH
* HO - CH, CH, -

KCI

55

The crude product is dissolved in dilute sodium hydroxide solution, adjusted to pH 6, from undissolved by-product (3-ammomethyl-5-amino-2A6-iriiodine-ben- zoic acid) freed by filtration and precipitated with hydrochloric acid.

E: ne further purification takes place by precipitating the cyclohexylammonium salt:

18 g of prepurified product are dissolved in 20 ml of methanol, decolorized with activated charcoal, filtered and mixed with 3 ml of cyclohexylane in 20 ml of methanol, a precipitate being formed. The cyclohexylam example! 13th

3 - {- Hydroxy (lh oxycarbonyl) -am i'iornet hy 1-5-hydroxyacetvlamino-2.4.6-triiodo-benzoic acid

R ₁ - (H CH. OH. R. = -CH, OH.

25.3 g 12bl (0.04 Mo!) In 50 ml Dimcthylacetamic are reacted at room temperature with 21.8 g (0.16 mol of acetoxyacetyl chloride and as in the example! described worked up.

A sticky product is obtained. Before separating the aqueous phase, the mass is on sth; 80 95 C heated. Crystallization then occurs.

The crude product (25 g) is dissolved in 75 ml of dry ethanol and 4 ml of morpholine are added whereby the morpholine salt of the desired product precipitates immediately. This is ge after 2 hours sucks. dissolved in water and decomposed by dropping in dilute hydrochloric acid at 50 ° C. After the suspension obtained has been heated to 80 ° C., you will sucked off new acid

Yield: 23 g (83.5 ° <. Of theory) Melting point: 186 C decomposition

TLC on silica gel with methyl ethyl ketone. Glacial acetic acid. Water. Ethanol = 20: 3: 3: 3. R ₁ = 0.48.

Equivalent weight:

Calculated ... 690:

found . . . 685.
C ₁₃ H ₁₃ J ₃ N ₂ O-:

Calculated ... C 22.63. J 55.18%:

found ... C 22.35. J 54.69 "" ,.

IO

Solubilities:

Slightly soluble in water and chloroform, slightly soluble in ethanol, very easily soluble in methanol. Na and MGA salts: Very easily soluble in water from 20 C. is

Example 14

3- (l'-Hydroxy-2'-buiox \ carbonyl l-aminomethyl-5-acetylamino-2.4,6-triiodo-benzoic acid

General formula

R ₁ = -CH (CH ₅ I-CH, -OH. R; = -CH _1. Η = 1

a) 3- (l'-Benzoyloxy-2'-butox \ carbonyl | -aminomethyl-5-amino-2.4.6-triiodo-benzoic acid

25th

54.3 g of 3-aminomethyl-5-amino-2.4.6-triiodo-benzoic acid (0.1 Mol) in 100 ml of water and 100 ml of 1N sodium hydroxide solution are added dropwise at 10-15 C with stirring at the same time mixed with 150 ml of a 16 °, oigen solution of 1-benzyloxy-2-chloroformyloxy butane (= Chloroformic acid - 1 - benzyloxy - 2 - butyl ester in acetone and 100 ml of 1N sodium hydroxide solution while observing a pH range of 10 11.

Working up is carried out according to the method described in Example 11 al. -, 5

Yield: 65.5% of theory.

Melting point: 81 C (sintering at about 60 C). DC R _f = 0.70.

C ₁₁ H ₂₁ J ₃ N ₂ O ₅ :

Calculated ... C 32.02. .1 50.67%: c found ... C 32.16. J 50.52%.

C ₁₅ H ₁ -I ₃ N ₂ O,
Calculated
found

Equivalent weight:
Calculated ... 702.03:
found ... 704.

C 25.66. J 54.23%: C 25.55. J 54.45%.

Solubility:

Soluble in boiling water, easily soluble in methanol and ethanol.

Na and MClA salts: easily soluble in cold water.

Example 15

3- (I'.3'-Dihydroxyisopropo \\ carbonyl-aminomeih \ l-5-acetylamino-2,4,6-triiodo-benzoic acid

R, = -CH (CH ₂ OH) ₂ . R ₂ = -CH.,. η - I
a) 5-Chloroformvloxv-1.3-dioxane

(1.3-formal-gl \ cerin-chloroformate = chloroformic acid-3.5-dio \ acyclohex> tester I.

To 99 g of phosgene in minor in KKX) ml of ether are at -H) to +10 C with stirring S3.2 g 1.3 - Forma! Glycerin (= 5 - hydroxy - 1.3 - dioxane) (0.8 mol) was added dropwise.

The temperature is allowed to rise slowly to 20 ° C. and then heated for a further 2 hours Reflux conditions.

The solvent is distilled off at normal pressure and the residue is then distilled in vacuo.

Boiling point: 106 108 C 14 mm Hg.

Yield: 95 g (71.5% of theory).

b) 3- (3 ^ ■ -Dioxacyclohexyloxycarbonyl-aminometh \ l-5-amino-2.4.6-triiodo-benzoic acid

CH, -O

40

Equivalent weight:

Calculated . .. 750.11:

found .. . 750

b) 3-U '-HydroxyO'-buloxycarbomII-aminomethylö-aceiylaminoOAö-tri.iodo-benzoic acid c

30 g of 3- (l -benzyloxy-2'-butoxycarbonyl) aminomethyl-5-amino ^ ao-triiodo-benzoic acid in 200 ml of glacial acetic acid and 16 ml of acetic anhydride are heated to 95 ° C., 2 ml of concentrated sulfuric acid are added and then treated by the method described in Example 11 c). Yield: 15 g (53.5% of theory). DC: R _f = 0.39.

Melting point: 147 C sinter. 176 C decomposition. (Sinters after suspending in boiling ethyl acetate the product at 162 C and decomposes at 186 C) R, = -CH

CH,

55 CH ₂ O

A solution of 6g 3-aminometh \! - 5-ami "' ¹ -2.4.6-triiodobenzoic acid {0.2 mol) in HXKl ml of water and 200 ml of 1N sodium hydroxide solution is at room temperature and pH 10 11 _un, mii a solution of 33.3 g of 5-Chlorformyfox \ -1.3-dio \ ar (0.2 mol) in KK) ml of acetone, and e _r stirring simultaneously with "20 (1'ml 1 N sodium hydroxide solution.

The mixture is stirred for some time and extracted d.inaci the reaction solution with ethyl acetate. The wäßriuc Layer is separated and "diluted in excess." Hydrochloric acid added dropwise. The resulting precipitate is filtered off with suction. in very dilute caustic soda solved, taking care that cir pH of 7 is never exceeded. The solution will be mii Treated activated charcoal, filtered and added dropwise to very dilute oabsaure, whereby the product precipitates

Yield: 117 g (87% of theory).

Melting point: (after recrystallization from abso lutem ethanol) Π4 183 C decompose.

C ₁₃ H ₁₅ J ₃ N ₂ O .:

Calculated .. C 23.1 7. J 56.49% - found ... C 23.46%. J 54.68%.

c) 3-1! .3 -DihvdroxyisopropoxycarbonyD-aminometh \ l-5-acetylamino-2.4.6-triiodo-benzoic acid

23.7 g 15h | (0.035 mol) are acetylated in 70 ml of ice cream with 70 ml of acetic acid and 0.1 ml of H, SO _a 11 in the usual way.

The reaction solution is evaporated in vacuo The residue is suspended in water, mi - Set N-sodium hydroxide solution to pH 11 and add

Hops of caustic soda for 15 minutes kept this pH. It is now heated to 70 80 ° C. for 20 30 minutes, practically complete Solution occurs.

The solution is filtered and acidified to pH 2. A small precipitate is filtered off. The 1-iltrate is evaporated to dryness in a vacuum.

The evaporation residue is extracted repeatedly with methanol. The extracts are combined with Activated charcoal decolorized and completely evaporated. The residue (24 g; melting point 94 KK) C) is dissolved in absolute ethanol, with 2.4 ml of cyclohexylamine added, whereupon the cyclohexylammonium salt of the desired product precipitates.

This salt is leached off, washed with a little ethanol, dissolved in water and washed with 200 ml of acidic cation exchanger resin IR-210 was charged Column run. The eluate is evaporated to dryness in vacuo.

The residue consists of the desired 3 - (Γ.3 '- dihydroxyisopropoxycarbonyl) - aminomethyl-5-acetylamino-2,4,6-triiodobenzoic acid.

Yield: 14.5 g (59% of theory).

Melting point 106 C.

TLC with eluent ethyl acetate / ethanol ammonia (25%) = 11: 7: 6. R _f = 0.40.
C ₁₄ H ₁ ^ N ₂ O-:

Calculated ... C 23.89, .1 54.08%:

aefundcn ... C 23.64. J 53.81%.

• Equivalent weight:

Calculated ... 704.00;
found ... 714.00.

Solubilities:

Soluble in water, methanol and ethanol

Example 16

3- (2'.3-Dihydroxypropoxycarbonyl) aminomelhyl-5-acetylamino-2.4.6-triiodo-benzocic acid R ₁ = - CH, - CH (OH) - CH ₇ OH. R, = - CH ,.

H = I

a) 3- (2'.3'-Dihydroxypropoxycarbonyl) aminomethyl-5-amino-2,4,6-triiodo-benzoic acid

45

54.3 g of 3-aminomethyl-5-amino-2.4.6-triiodo-benzoic acid (0.1 mol) in 500 ml of water and 100 ml of 1 N sodium hydroxide solution are at 10 - 15 C and pH 10 up to 11 at the same time dropwise with 19.5 g chloroformic acid - 1,2 - isopropylidene - glycerol ester (= 4 - chloroformyloxymethyl - 2,2 - dimethyl -1.3 - dioxolane) in 100 ml of acetone and mixed with 100 ml of 1N sodium hydroxide solution. The resulting raw product is isolated as described in Example 6a), dissolved in dilute sodium hydroxide solution, brought to pH 11 and after one hour reprecipitated by dripping into dilute hydrochloric acid. This is without any further special Measure the ketal protecting group of the isopropylidene radical - split off, and the hydroxy functions are released. The split off acetone is automatically used during the drying process, which is necessary anyway removed.

Yield: 47.25 g (71.5% of theory).

Melting point: 125 C sinter, 187 C decompose.

C ₁₂ H ₁₃ J ₃ N ₂ O ,,:

Calculated ... C 21.77, J 57.51%;
found ... C 22.21. .1 56.36%.

b) 3- (2 '.. ^' - Dihydroxypropoxycarbonyl) aminomethyl-5-acetylamino-2,4,6-triiodo-benzoic acid

36.4 g of 3- (2 ', 3'-Dhydroxypropoxycarbonyl) -aminoinethyl-5-amino-2,4,6-triiodo-benzoic acid c (0.055 mol) in 260 ml of glacial acetic acid and 28 g of acetic anhydride (0.075 mol) are heated to 95 ° C. with stirring, with 10 drops of concentrated sulfuric acid are added, the mixture is heated for 1 to 3 hours and then in a vacuum Dry evaporates. The residue crystallizes on trituration with water. He's sucked in Dissolved dilute sodium hydroxide solution, brought to pH 11 and heated to 50 C. By adding sodium hydroxide solution, a pH of 11 is maintained until the Acetoxy groups are completely saponified. The solution is then acidified. The eliminated Product gradually crystallizes. It is recrystallized from water.

Yield: 23.5 g (61% of theory).

Melting point: 172 ° C sintering. 185 'C decomposition.

C ₁₄ H ₁₅ J ₃ N ₂ O-: C 23.89. j I 54.08%; Calculated ... C 23.28. J I 53.44%. found ... chi: Equivalent weight . 704.00; Calculated .. . 700 Found ..

D.C: Laufmiltel as in example 1 b). R, = 0.29.

Solubilities:

Slightly soluble in cold, slightly soluble in boiling water, soluble in cold ethanol, slightly soluble in methanol and boiling ethanol, slightly soluble in chloroform.
Na and MGA salt: Easily soluble in cold water.

Example 17

3- ( _/ ; -Methoxyalkoxycarbonyl) -aminomethyl

5-acelylamino-2.4.6-triiodobenzoic acid
R ₁ = - CH ₁ - CH, - O - CH ₃ . R, = - CH ,.

/ i = l

a) 163.2 g of 3-aminomethyl-5-amino-2.4.6-triiodobenzoic acid (0.3 mol) in 1000 ml of water and 300 ml of 1N sodium hydroxide solution are at pH 10 11 with 41 g Fi-methoxyethyl chloroacidate (0.3 mol) in 100 ml of acetone and 300 ml of 1N sodium hydroxide solution.

The product obtained is isolated by a method similar to that described in Example 11 a) and cleaned.

Yield: 181 e (94% of theory).
Melting point: 182 "C. R _f = 0.63.

C ₁₂ H ₁₁ J ₃ N ₂ O ,:
Calculated
found

C 22.31. J 58.94%:
C 22.29. J 58.69%.

b) 3 - (, .- Methoxyethoxycarbonyl) aminomethyl-5-acetylamino-2,4,6-triiodo-benzoic acid

39 g .V-methoxyethoxycarbonylaminomethylo-amino-2,4,6-triiodo-benzoic acid in 180 ml of glacial acetic acid and 30 ml of acetic anhydride are concentrated with 0.1 ml Sulfuric acid was added and the mixture was stirred on the steam bath for 3 5 hours. The work-up takes place according to the method described in Example 2. the

29

/ OP

Purification takes place via the ammonium salt, which is dissolved in concentrated aqueous solution with ammonium chloride is salted out.

Yield: 29.2 g (70% of theory).

Melting point: 130-135 "CDC: R ₁ = 0.46.

C ₁₄ H ₁₅ J ₃ N ₂ O ,,:

Calculated ... C 24.44, J 55.34%; found ... C 24.13. J 55.82%.

Equivalent weight:

Calculated ... 687.99; found . .. 690.

Solubilities:

Soluble in boiling water, in methanol and ethanol.

Na and MGA salt: Easily soluble in cold water.

Example 18

The following compounds of the general formula I were obtained analogously:

a) R ₁ = - CH ₂ - CH ₂ - O - CH ₃ . R ₂ = - C ₂ H ₅ . 11 = 1

Yield: 73%. R _f = 0.56.

Melting point: (after suspending in boiling allyl acetate) 205 - 210 C.

C ₁₅ H ₁₇ J ₃ N ₂ O ,,:

Calculated ... C 25.66. J 54.23%: found ... C 25.88. J 54.03%. Equivalent weight:

Calculated . . . 702.03:

found . . . 704

Slightly soluble in water, soluble in ethanol, slightly soluble in methanol.

Slightly soluble in water and chloroform, slightly soluble in ethanol.

Na- and MGA-SaIz: Easily soluble in everything Water.

B) Hexaiodine compounds: General formula III.

Example 19

1.2-bis- (3-carboxy-5-acetylamino-2.4.6-triiodobenzylaminocarbonyloxyl-ethane

_{R 1} = - CH 1 - CH 1, R ₁ = - CH ₃ . / 1 = - 2

al 1,2-bis- (3-carboxy-5-amino-2,4,6-triiodobenzylaminocarbonyloxy) -älhan

54.5 g of 3-aminomelhyl-5-amino-2,4,6-triiodo-benzoic acid. suspended in 80 ml of dimethylacctamide are added dropwise with stirring with 10.25 g of 1,2-bis (chloroformyloxy) ethane (Ethylene glycol - bis-chloroformated) (0.055 mol) added. Immediately a clear solution. This is heated to 70 ° C. for 35 hours, then to half in vacuo evaporated their volume and stirred into 400 ml of water. The product which precipitates out gradually crystallizes. It is dissolved in aqueous ammonium hydrogen carbonate solution and again with hydrochloric acid failed. Suspending in hot isopropanol and dilute hydrochloric acid gives the product cleaned.

Melting point: i45 C.

TLC: solvent as in example la b etc. R ₁ = ■ - 0.43.

b) R, - -CH, CH, - O R, = -CH, - OH. n ^

CH ;.

Yield: 91%.
Melting point: 206

208 CR. · = ■ -0.49.

Calculated ... C 23.89. J 54.08%: found ... C 23.78, J 53.81%.

Equivalent weight:
Calculated ... 703.99: found ... 707.

Soluble in boiling water, easily soluble in methanol and ethanol.

Na and MGA salt: Easily soluble in cold water.

c) R ₁ = - CH ₂ - CH ₂ - O - CH ,. R ₂ = - CH ₂ - O - CH ₃ . π =

Yield: 85% of theory. Melting point: 193-195 C. R _f = 0.57.

C ₁₅ H ₁ J ₃ N ₂ O ,:

Calculated ... C 25.09. .1 53.02%; found ... C 24.84. J 52.37%.

Equivalent weight:

Calculated ... 718.02; ucfound ... 718.

Calculated
found

C 19.99. J 63.36%
20.85. .1 62.72%.

45

55 hl 1,2-bis (3-carbo \ y-5-acetyhimino-2.4. <> \ Riiodbcnzylaminocarbonyloxy) -älhan

20 g of the "compound described above according to" Example 19al are in SOmI Hisessig and 2m Acetic auhysride suspended, with stirring au Heated to 95 C and mixed with 0.1 ml of concentrated sulfuric acid. The mixture is stirred at 95 ° C. for a further 2 hours The educt dissolves quickly and later the acetylated compound crystallizes out. This will au aqueous ammonium hydrogen carbonal solution with hydrochloric acid, then in hot isopropano suspended, suction filtered and washed with water. Yield: 144 g (67.5% of theory).

Melting point: 246 C (decomposition). DC: R _f = 0.3i

60 Calculate!
found

C 22.42. J 58.29%:
21.73. J 57.57%.

Solubility:

Insoluble in water. Methanol. Ethanol Chloroform.

Na and MCiA SaI ?:> 1001> 100 ml water 20 C

Example 20

1,3-bis (3-carbuxy-5-acetylamino-2,4,6-thiiodobenzylaminocarbonyloxy (-propane

R ₁ = - CH, CH, CH, -, R ₂ = - CH ₃ . η = 2

a) 1,3-bis (3-carboxy-5-amino-2,4,6-triiodobenzylaminocarbonyloxy !-propane

IO

54.3 g of 3-aminomethyl-5-amino-2,4,6-triiodo-benzoic acid are analogous with 11.05 g of 1,3-bis (chloroformy! oxy) propane (1,3-propylene glycol bis-chloroformate) Example 19a) implemented. Cleaning: Dissolve the crude product in aqueous sodium hydroxide solution, but not pH 7 exceed, filter off insolubles, extract the solution 4 times with chloroform and 3 times with ethyl acetate, Remove organic solvent from the aqueous layer and acidify the product with hydrochloric acid precipitate, then suspend in boiling isopropanol and fall from dilute sodium hydroxide solution with dilute hydrochloric acid.

Yield: 48.2 g (79.5% of theory).

Melting point: 145 C sintering, 194 C decomposition. R _f = 0.67.

C ₂₁ H ₁₈ J ₁₁ N ₄ O ₈ :
Calculated ..
found ..

C 20.75, J 62.63%: C 20.80. J 62.36%.

C 23.10. J 58.57%: C 22.85. J 58.65%.

Solubilities:

Slightly soluble in water and chloroform, very easily soluble in methanol and ethanol. Na and MGA salts:> K) Og / 100 ml water from 20 C.

Example 21

1,4-bis (3-carboxy-5-acetylamino-2,4-triiodobenzylaminocarbonyloxy (-butane

R ₁ = - (CH ₂ ) ₄ -, R ₂ = - CH ₁ . / 1 ---- 2

a) Implementation of 3-aminomethyl-5-amino

2,4,6-triiodo-benzoic acid (54.5 g) with 1,4-bis (chloroformyloxy) butane (11.8 g) analogously

Example 19a) and 20a)

Yield: 28.1 g (45.6% of theory). Melting point: 235 C decomposition. D.C .: R, = 0.39.

b) Reacting 24.6 g of 21a) with acetic anhydride (8 ml) in 96 ml of glacial acetic acid in the presence of 0.5 ml of concentrated Sulfuric acid analogous to Example 19b |

Cleaning: dissolve in 15% ammonium hydroxide solution. Cases by dropping in diluted Hydrochloric acid. Dissolve in a little ammonium hydroxide, salt out, the ammonium salt by adding ammonium chloride, Filter off the salt. Dissolve in water. Decompose with dilute hydrochloric acid. Solve in a little sodium hydroxide solution (up to pH 7). filter. Decolorize the filtrate with charcoal and acidify with hydrochloric acid.

Yield: 15.3 g (53% of theory).

Melting point: 178 C sinter. 212 C decompose. R _f = 0.46.

C ₂₁₁ H ₂₄ J ₁₁ N ₄ O ₁₀ :
Calculated
found

Equivalent weight:
Calculated ... 607.91:
found ... 610.

b) bis-5-acetylamino compound

Production analogous to Example 19 b). Suspending in hot isopropanol is omitted here.

Yield: 82.5%.

Melting point: 190 C sinter. 210 C decomposes. R, = 0.49.

C ₂₅ H ₂₂ J ₁₁ N ₄ O ₁₀ :
Calculated .
found .

35

40

45 C 23.76. J 57.94%:
C 23.43, .1 58.06%.

Equivalent weight:

Calculated .. 656.96:
found .. 648.

Solubilities:

Slightly soluble in water and chloroform, slightly soluble in methanol and ethanol.
Na salt:> HK) g 100 ml water at 20 C.
MGA-SaIz: - 50 g KK) ml water at 20 C.

Example 22

1.6-bis- (3-carboxy-5-acctylamino-2.4.6-triiodobenzylaminocarbonyloxyhexane

R ₁ = - (CH ₂ ) ,, -. R ₂ = - CH 1, 11 = 2

a) 54.5 g of 3-aminomethyl-5-amino-2.4.6-iriiodobenzoic acid are reacted with 13.9 g of 1,6-bis (chlorofonnyl) hexane analogously to Example 20a).

Yield: 32 g (51%).

Melting point: decompose 234 C, R ₁ = 0.43.

C ₂₄ H ₂₄ J ₁₁ N ₄ O ₈ :
Calculated
found

Equivalent weight:
Calculated . .. 628.96:
found . .. 633.

b) 28.8 g of 22a) are mixed with 9.2 ml in 112 ml of glacial acetic acid Acetic anhydride reacted in the presence of 0.5 ml of sulfuric acid.

Dent: 21 t; (68% of theory).
DC: Rf = 0.47.

Melting point: 170 C sinter. 220 225 C decompose.

C 22.92. .1 60.54%;
C 22.61. .1 60.42%.

C ₂₂ H ₂₀ J ₁₁ N ₄ O _x : . C. 21.48. .1 61 , 93%: Calculated . . . C. 21.95. .1 61 .30%. found. .

65 C _2n H ₂₈ J ₁₁ N ₄ O ₁₁₁ :

Calculated ... C 25.06. .156.74%:
found . .. C 25.23. J 56.71%.

Equivalent population:

Calculated . . 670.99:
found . . 672.

Solubilities:

Insoluble in water and chloroform, very easily soluble in methanol and ethanol.
Na- and ΝΗίΛ-Sal /:> K) Og K) OmI water \ 1111 20 C.

• J «3

Example 2i

LS-bis-O-carboxy-S-acetylamino-IAo-triiodobenzyIaminocaiJonyloxy) -3-oxa-pentane

K ₂ - um. ,, η - = _

a) 0.1 mol of S-aminomethyio-amino ^ ao-triiodobenzoic acid in 500 ml of water and 100 ml of 1N sodium hydroxide solution are simultaneously mixed with 0.05 moles of freshly distilled 1,5-BiS- ^ hIorformyloxy at 10-15 C with stirring ) -3-oxa-pentane (= diethylene glycol bischiorformate) in 50 ml of acetone and 100 ml of 1N sodium hydroxide solution are added, the pH of the solution being kept between 11 and 11. Stirring is continued for ¹ / Γ- 1 hour at room temperature, set the pH to 7, and extracted with chloroform and ethyl acetate. The aqueous layer is freed from adhering organic solvent by evacuation and then acidified, whereupon the product precipitates.

Yield: 62.6 g (99% of theory).

Melting point: 135 C sinter, 91 C decompose.

Calculated ... C 21.21, J 61.12%: found ... C 20.76. J 60.39%.

Equivalent weight:

Found 635;

calculated with 1.5 MoI water of crystallization ... 636.24.

Water content:

Found 1.9%;

calculated for 1.5 H ₂ O 2.2%.

b) 56 g of 23a) are acetylated.

Yield: 47 g (78.5% of theory). R, = 0.48.

Melting point: 183 C sinter. Decompose 210 C.

_25th

30th

35

40

C 23.48. J 57.25%: C 23.20,. I 57.10%.

Calculated
found

Equivalent weight:

Calculated ... 664.96:

found ... 660.

Solubilities:

Slightly soluble in water and chloroform, easily soluble in methanol and ethanol.

Na and MGA salt:> K) Og / 100 ml water at 20 C.

Example 24

1.8-bis (3-carboxy-5-acetylamino-2,4,6-tiiodobenzylaminocarbonyloxy) -3,6-dioxa-octane

R ₁ = -CH ₂ CHj -O-CH ₂ CHi -O-CHiCH, ^K C'H

60 Subsequently, the temperature envelope while still jeeivva 3R minutes at 0. 10. 20 C and 2 hours _bej U C. The solvent is distilled off and fractionally distilled twice _the residue in vacuo.

Boiling point: 160 iol L 2 mm hu.

Yield: 104 g (47.5% of theory !.

_b) j 8.ßi _s - (3-carbox \ -5-amiiio-2.4,6-tnjodhenzv! amino-carbon \ loxYl-3.6-dioxa-octane

54.3 g of 3-aminomethyl-5-amino-2,4. () - iriiodobenzoic acid (0.1 mol) are analogous to Example 23io with 1175 g (0.05 mol) of 1,8-bis (chloroformyloxy) -3.6-dioxa-octane (24a) implemented.

Yield: 52.25 g (81% of theory).

The; The crude product obtained becomes crystalline on trituration with water. It is precipitated from dilute sodium hydroxide solution by dropping it into dilute silicon dioxide: 47 g of purified product.

Melting point: 112 C sinter. 133 C / replace.

TLC: R, = 0.63.
q _h j jsj ο

"Calculated ... C 22.35. .1 59.03%: found ... C 22.38. J 59.30%.

_c) 44 _{g of} 24b) (0.034 mol) are acetylated in 190 ml of glacial acetic acid with 116 ml of acetic anhydride and 0.7 ml of concentrated sulfuric acid.

The crude product is reprecipitated from dilute sodium hydroxide solution with dilute hydrochloric acid and over the The cyclohexylammonium salt is purified by adding an alcoholic solution of the acid with 5.5 ml of cyclohexylamine added, the salt formed can crystallize for 24 hours, finally. dissolved in water and with Hydrochloric acid falls.

Yield: 31 g (65% of theory).

Melting point: 203 C decompose.

TLC R ₁ = 0.46.

Calculated
found

C 24.48. J 55.42%: C 24.58. . I 54.55%.

a) 1.8-bis (chlorformylo.xy) -3.6-dio \ a-octaii (= Triethylene glycol bis-chloroformate)

To 199.5 g of phosgene (2 mol), η KXX) ml of ethyl ether tmp t while stirring. -IO to 0 C 120 g of T, ialhylene glycol (0.8 moles).

Equivalent weight:
Calculated ... 686.99:
_ue found ... 697.

Loses:

Very little soluble in water and chloroform, very easily soluble in methanol and ethanol. Na- and MGA-SaIz:> 100 u 100 ml of water at 20 C.

Example 25

1.2-bis- (3-carboxy-5-hydroxyacctylamino-2.4,6-triiodo-benzyI-aminocarbonyloxyethane

^R i ⁼ "-CH, -CH ₂ -. R ₂ = CH ₂ OH. / 1 - 2

10 g of K2-bis- (3-carboxy-5-amino-2,4,6-tri. | Od-benzylaminocarbonyloxyMithane (example 19a) (O.OO8 mol) in 60 ml of Dimcthylacetamid are partially Distilling off the solvent and then dehydrated at 23 ° C. dropwise with 4.35 g aceloxyacetyl chloride 10,032 mol) added. The reaction solution was stirred for 10 hours, then in 150 ml Poured water by adding 35 ml of 1 N-Ni tronlaujiu on pll Il. -ebracht. 1 hour at 40 ° C

held, then filtered and diluted in 50 ml Stir in hydrochloric acid.

The product fails.

Yield: 9 g (85% of theory).

Melting point: 20 C decomposition. DC: R ₁ ■ - 0.33.

C ₂₄ H ₂₀ J ₀ N ₄ O ₁₂ -, H ₂ O:

Calculated ... C 21.29, J 56.23, H, O 2.66%:
Found ... C 21.18, J 55.75, H ₂ O 2.72%.

Na and MGA salts: easily soluble in water.

Example 26

1,2-bis (3-carboxy-5-methoxyacetylamino-2,4,6-triiodo-benj: ylaminocarbony! oxyHithane

R, = - CH ₂ - CH ₁ -,
R, = - CH ₂ - O - CH ₃ , ti = 2

12 g of 1,2-bis (- carboxy-5-amino-2,4,6-triiodo-benzylaminocarbonyloxy) ethane in 60 ml of dimethylacetamide are analogous to Example 25 with 2.7 methoxyacetyl chloride implemented.

Yield: 13.1 g (97% of theory).

Melting point: 190 C decomposition. DC: R _f = 0.42.

C _2n H ₂₄ J ₁₁ N ₄ O ₁₂ :

Calculated ... C 23.20, J 56.57%;
found ... C 22.94 _V J 56.85%.

Na and MGA salts: easily soluble in water.

Example 27

1.S-Bis-P-carboxy-S-hydroxyacetylamino-2,4,6-triiodo-benzylaminocarbonyloxy) -3-oxa-pentane

R. = - CH ₁ CH ₂ - O - CH ₁ CH, -.
R ₂ = - CH ₂ OH, n = 2

12.45 g of 1,5-bis- (3-carboxy-5-amino-2,4,6-triiodobenzylaminocarbonyloxy) -3-oxa-pentane (Example 23a) are analogous to Example 25 with 6.8 g of acetoxyacetyl chloride implemented and processed.

Yield: 11.6 g (85.3% of theory).

Melting point: 213-214 ° CDC: R _f = 0.27.

C ₂₆ H ₂₄ J _n N ₄ O _n :

Calculated ... C 22.93, J 55.90%:
found ... C 22.54, J 55.22%.

Equivalent weight:
Calculated ... 681;
found ... 675.

Na and MGA salts: easily soluble in water.

Forming examples

The 3-alkoxycarbonylaminomethyl-5-acylamino-2,4,6-triiodo-benzoic acids of the general formula I are according to their preferred use as uro / vasography or intravenous cholecystography devices usually processed into injectable or infusible saline solutions.

Solutions of sodium or alkanolamine salts are particularly suitable for this purpose Mono-, di- and poly-hydroxyalkylamine salts, such as for example the N-methylglucamine, N-methylxylamine, 1 -Methylamino ^^ - propanediol and diethanolamine, monoathanolamine salts.

mixtures of sodium and alkanolamine salts are used, for example N-methylglucamine salts with an addition of sodium salt or mixtures of an N-methylglucamine and monoethanolamine salt with the aim of To create injection solutions that are as well tolerated as possible and at the same time have the lowest possible viscosity.

Tris (hydroxymethyl) aminomethane is occasionally added in small amounts for buffering, jo By choosing the cation and the salt concentration, an optimal adjustment can also be made in each case to the various specific uses

B e i s ρ i e 1 1

Urography agents

Aqueous salt solutions are used for ography monovalent 3-alkoxycarbonylaminomethyl-ϊο S-acylamino ^ Ao-triiodo-benzoic acid of the general Formula I with an iodine content of about 150-400 mg ml.

Recipe 1 a)

1 542.5 g

2. N-methyl-glucamine 134.4 g

3. Sodium hydroxide 4.0 g

4. Ethylcndianiine tetraacetic acid disodium salt (EDTA-Na ₂ ) 0.1 g

5. Water (double distilled), ad "KHX" ml

The saline solution is released according to the recipe above. by dissolving substance 4 in a little water, adding substances 1, 2 and 3 one after the other, the solution obtained after stirring is adjusted to pH 7.1 i 0.2, made up to 1000 ml, filtered.

Filled in ampoules of 10, 20 and 30 ml, melted under nitrogen and then in the heat sterilized: 10 20 minutes 1 IOC. Iodine content: 3 (X) mg / ml.

Recipe 1 b)

S-ethoxycarbonylaminomethyl-S-hydroxyacetylamino ^ Ao-triiodo-benzoe-

acid 602 g

Methyl glucamine 97.6 g

Monoethanolamine 23.7 u

EDTA-Na, 0.1 g

Water (double distilled), ad KXX) ml

Preparation of the solution analogous to la). Iodine content: 340 mg / ml.

Example 2

Vasographic agents

These usually also consist of salt solutions of compounds with / 1 = 1, in some But cases also from salt solutions of compounds with 11 = 2. The latter have the advantage of one slightly lower Osinolian pressure, based on the same iodine content. The concentration and the composition the cations in these vasographic agents vary widely, for optimal matching to the various objectives of the vaso-

24

graphy: anginocardiography, cerebral anginography, aortography, Plebography (venography), l \ mphography, Hystero-salpingiography, Splenoporiographic i.a. m.

Iodine content around! 50 - 5 (X) mg / ml.

For infusion solutions, dilute saline solutions are usually used: 45 150 ma J / ml.

Recipe 2a)

3-methoxycarbonylaminomethyl-S-hydroxyacetylamino ^ Ao-triiodo-

benzoic acid 693.5 g

Methyl glucamine 78.i g

Sodium hydroxide 24 g

Tris (hydroxymethyl) aminomethane ... 6.3 ü

EDTA-Na ₂ ". 0.1 g

Water (double-distilled), ad 1000 ml

Iodine content: 400 mg / ml.

Recipe 2 b)

3 - (// - Methoxyethoxyearbonyl) -aminomethyl-5-hydroxyacetylamino-

2,4,6-triiodo-benzoic acid 555 g

Methylxylamine 47.7 g

l-methxlamino-2.3-propandio! 26.3 g

Sodium hydroxide IO s>

EDTA-Na ' ₂ 0.1 g

Water (double-distilled), ad 1000 ml

Iodine content: 4 (X) mg / ml.

Recipe 2c)

1.2-bis- (3-carboxy-5-hydroxyacetylamino-ZAö-triiodo-benzylamino-

carbonyloxy) ethane dihydrate 890 g

N-methylglucamine 85.5 g

1-methylamino-2,3-propanediol 46.1 g

Sodium Hydroxide 17 54

EDTA-Na ₂ 0.2 >>

Water (double-distilled), ad 1 250 ml

Iodine content: 4 (K) mg / ml.

Example 3 Cholczystographie-ZCholangiographicmiUel

These consist of aqueous salt solutions of bis-ft-carboxy-S-acylamino- ^ Aö-trijod-benzylamino-

718

carbonyloxyl-alkanes, where η is -2 , with an iodine content of * usually about 150-400 mg ml. Infusion solutions are more dilute: 45-150 mg j ml.

Recipe 3a)

1.5-bis- (3-carboxy-5-acetylamino-2.4.6-triiodo-benzylaminocarbonyloxy) -

3-oxa-pentane r> 24.3 g

N-i \ 1ethylglucamine 115 g

Sodium hydroxide Xy

EDTA-Na ₂ <M g

Water (double distilled). ad K) OO nil

Iodine content: 3 (X) mg / ml.

Recipe 3 b)

1.4-bis (3-carboxy-5-acetylamino-2.4.6-triiodo-benzylaminocarbonyl-

ox \ (-butane 259 g

N-methylglucamine 57.4 µ

Sodium hydroxide 4.0 o

EDTA-Na ₂ Ol g

Water (double distilled). ad KKK) mi

Iodine content: 150 mg; ml.

Recipe 3c)

1.8-bis (3-carboxy-5-acelylamino-2.4.6-triiodo-bcnzylamiiiocarbonyl-

oxy) -3.6-dioxa-oclane 27Ig

N-methylxylamine 32.Ig

Sodium hydroxide 0.S u

EDTA-Na ₂ Ol µ

Water (double distilled). ad HK) OmI

Iodine content: 150 mg, ml.

Recipe 3d)

1.3-bis (3-carboxy-5-acetykimino-2.4.6-triiodo-benzylaminocarbonyl-

oxy) propane 85.4 g

N-methylglucamine 25.7 u

EDTA-Na, 0.05 "

Water (double-distilled), ad K) OO ml

Iodine content: 50 mg'ml.

Claims (5)

Patent claims:
1. 3-Alkoxycarbonylaminomethyl-5-acylamino-2,4,6-triiodobenzoic acids of the general formula 1 R ₁ -CO-NH I CH, -NH-CO-O- wherein R _{1 is} either a monovalent alkyl radical with 1-4 carbon atoms, a hydroxyalkyl, dihydroxyalkyl or alkoxyalkyl radical with 2-3 carbon atoms or a divalent alkylene radical with 2 to 6 carbon atoms [= - (CH ₂ ), _ ₆ -] or a corresponding mono-, di-, tri- or tetraoxa-alkylene radical, / 1 the number 1 if R _{1 is} monovalent, and the number 2 if R _{1 is} divalent, and R, alkyl, hydroxyalkyl or alkoxyalkyl, each having 1 to 3 carbon atoms, and their physiologically well tolerated alkali, alkaline earth and alkanolamine salts. 2. 3 - Methoxycarbonylaminomethyl 1-5 - acetylamino-2,4,6-triiodobenzoic acid and their physiologically well-tolerated salts. 3. 1,2-bis- (3-carboxy-5-hydroxyacetylamino-2,4,6 - triiodobenzylamino-carbonyloxy) - ethane and its physiologically well-tolerated salts. 4. Process for the production of the components used as shading in Rontgenkor.trastm.mittel Usable 3-alkoxycarbonylaminomethyl-5-acylamino-2,4, (5-triiodo-benzoic acids and their salts according to claim 1, characterized in that one known per se Catfish in any order a 3-aminomethyl-5-amino- or -5-nitrobenzoic acid derivative of the general formula IV 45 COOH (IV) CH, -NH, 55 wherein A is an amino or nitro group and X ^. X ₄ and X ₍ , iodine, chlorine or hydrogen atoms mean, with a reactive carbonic acid ester of the general formula V [Y-CO -QI ₁₁ -R ₁ " (V) wherein Y is a chlorine, bromine, .lodatom or an aryloxy radical, R ₁ "either a monovalent alkyl radical with 1 - · 4 carbon atoms, a hydroxyalkyl, dihydroxyalkyl or alkoxyalkyl radical with 2 to 3 carbon atoms, the hydroxyl groups of which are usually through Esterification, an easily cleavable ether function or masked by acetal or ketal functions, or finally a divalent alkylene radical with 2 - 6 carbon atoms or a corresponding mono-, di-, tri- or tetra-oxaalkylene radical and η the number 1 if R ₁ "is monovalent, and the number 2, when R ₁ " is divalent, means, or with phosgene and an alcohol R ₁ "- OH to form an N- (3-carboxybenzyl) urethane of the general formula VI COOH X "IX ₂ CH ₁ -NH-CO-O- (Vl) converts, if necessary A and X ₂ , X ₄ and / or X ,, converted by reduction into an amino group or into hydrogen and the aromatic nucleus triiodinated, and the aromatic amino group acelicrt by reaction with an acid of the general formula VIl R, "- COOH (VIl) where R ₂ "is an alkyl radical with 1-3 carbon atoms or a hydroxyalkyl radical with 1-3 carbon atoms, the hydroxyl group of which is masked by esterification or an easily cleavable ether function or represents an alkoxyalkyl radical with 1-3 carbon atoms , and with dehydrating medium or with an anhydride or chloride of the same acid. 5. X-ray contrast media, especially for intravenous use: ¹ . Application containing 3-alkoxycarbonylaminomethyl-5-acylamino-2.4.6-triiodo benzoic acid or a physiologically well-tolerated alkali metal, alkaline earth metal and alkanolamine salt according to claim 1 as switching components.