LT3251B - Process for preparing trijodobenzene compounds - Google Patents

Abstract

The invention concerns a compound having formula (I). Said compound can be used as a contrast product.

Description

The present invention is one of the methods of producing contrast media for X-rays.

Known as contrast media, black benzene compounds containing iodine atoms and other substituents on the benzene ring are selected to give the compounds sufficient solubility in water, on the one hand, and, on the other, to provide sufficient tolerance to the human body. for these compounds.

To that end, French patent no. A-2-053037 discloses carbamoyliodobenzene compounds having at least one N-oxyalkyl group and at least two hydroxyl groups.

an example of this class of compounds is the metrizamide nonionic compound having several hydroxyl groups (see Invest. Rad., 15, Supplement 65 323 328, 1980).

However, this compound appeared to be poorly stable in aqueous solution.

Other non-ionic compounds having an oxyacylamide group are known, such as Jonversol, which is described in European patent no. 0083964.

However, this compound is also unstable in aqueous media, which causes problems in obtaining an injectable solution.

solubility tolerance, it is an object of the present invention to provide compounds having good solubility to form novel non-ionogenic compounds of high human body, high aqueous stability and low viscosity of aqueous solutions.

This object is achieved by the proposed method of obtaining triiodobenzene compounds of the formula:

Ri

CO-N-Ri

I

Ra l

CH CHa OH (I) wherein R _x

CH a OH represents monohydroxy-C ₁ -C ₄ alkyl, dihydroxy-C ₁ -C ₄ alkyl;

R ₂ - represents hydrogen or _Cl-C4 alkyl;

R ₃ represents hydrogen, monohydroxy-C ₁ -C ₄ alkyl or dihydroxy-C ₁ -C ₄ alkyl.

This method is based on the alkylation of an amino of formula II:

J

COC1: id with chloro anhydride of formula RCOC1 for the formation of compound of formula IV:

; ill), and

(IV) ch ₂ oh /

where R stands for CH \

CH ₂ OH wherein the hydroxyl groups are protected;

the resulting compound of formula (IV) is treated with an amine of formula HN-R ₄ '(V),

1 and _{2 for the} compound of formula (VI):

wherein R ₂ to R ₂ have the meanings indicated above and then, if necessary, alkylating the compounds of formula VI with an alkylating agent R ₄ 'Z where R ₄ ' = R ₃ ', except hydrogen, Z represents chlorine in the presence of a base - sodium methylate followed by deprotection of CH (CH ₂ OH) ₂ .

The novel products of the present invention are used in humans and animals for radiographic examination and can be incorporated into pharmaceutical compositions; preferably, the pharmaceutical form is an aqueous solution of the compounds.

As a rule, the total amount of the compounds of the formula I in aqueous solutions is from 5 to 100 g in 100 ml of solution, and the amount of such solutions to be administered ranges from 1 to 1000 ml.

Aqueous solutions of compounds I may contain various additives, for example:

- sodium chloride at a concentration of 0.10 to 10 mmol / l,

- ethylenediaminotetracetic acid disodium salt (EDTA), in a concentration of 0,1 to 2 mmol / l,

- sodium citrate in a concentration of 0,1 to 10 mmol / l,

- heparin, in doses of 10 to 100 units per 100 ml of solution.

These compositions may be administered by a variety of routes conventionally used to administer nonionic iodinated contrast agents. Thus, they may be administered enterally or parenterally, intravenously, into an artery to provide opacity to the cavities, and, inter alia, to the subarachnoid area.

The following is an example of a composition of the present invention.

COMPOSITION

The compound of Example 65g

Water for injection up to 100 ml as needed.

The following examples illustrate the preparation of compounds of formula I.

EXAMPLE I

Preparation of 5- [3-oxy-2- (oxymethyl) -N- (2,3-dioxypropyl) propionamide] -N ', N-bis (2-oxyethyl) 2,4,6-triiodoisophthalamide.

a) Preparation of 5- [2-isopropyl-1,3-dioxan-5-carboxamide] -2,4,6-triiodoisophthaloyl dichloride.

Dissolve 137 g of 5-amino-2,4,6-triiodophthalyl chloride (0.23 mol) in 460 ml of dimethylacetamide and add 110 g (0.57 mol) of 2-isopropyl-1,3-dioxane-5-carbonic acid chloro-anhydride. The reaction mixture was stirred for 4 days under argon at ambient temperature. Dimethylacetamide is distilled under vacuum. The resulting oil is extracted with 3 L of ethyl acetate and washed twice with 1 L of water. The organic phase is dried and evaporated to dryness. The product is crystallized from 200 ml of methylene chloride. Filtration gave 110 g of a solid. Yield 64%.

TLC: SiO ₂ , methylene chloride Rf: 0.13.

(60P 254) SiO ₂ ether / petroleum ether 50/50, Rf: 0.52.

b) Preparation of 5- [2-isopropyl-1,3-dioxane-5-carboximido] -N ', N''-bis- (2-oxyethyl-2,4,6-triiodoisophthalamide).

Dissolve 130 g of the product obtained in (a) (0.173 mmol) in a solution of 750 ml of dimethylacetamide and 75 ml (0.534 mmol) of triethylamine. 33.7 g (0.552 mole) of ethanolamine are added dropwise to the reaction mixture. The reaction mixture was then stirred at ambient temperature for 3 hours. The triethylamine hydrochloride is separated by filtration and the dimethylacetamide is distilled off in vacuo. The resulting oil is crystallized from 11 water. The product is filtered off and dried in vacuo. Yield 95%.

Thin layer chromatography:

SiO ₂ , methylene chloride / methanol 9/1, Rf: 0.25.

(60 F 254) SiO ₂ , methylene chloride / methanol 8/2, Rf: 0.67.

Iodine content: found 45.6%, theoretical 47.6%.

Purity (HPLC detection, HPCL hypersil C8 5 mk 15 cm, NaH ₂ PO ₄ 0.01M = 50, methanol = 50): 97%.

c) Preparation of 5 - [(3-oxy-2-oxymethyl) -N- (2,3-dioxypropyl) propionamide] -N ', N' '- bis-2-oxyethyl-2,4,6-triiodoisophthalamide.

To a suspension of 100 g (0.0125 mol) of the product obtained in step b) is added 350 ml of ethylene glycol in 125 ml (0.5 mol) of 4N sodium methylate at 60 ° C, followed by 65 g (0.625 mol) of l-chloro-2 , 3-propanediol. After one hour at 60 ° C, the reaction mixture thickens. Adds 100 mL (0.4 mol) of 4N methylate and 55.2 g (0.5 mol) of l-chloro-2,3-propanediol. The mixture is kept overnight at 60 ° C. A further 31 ml (0.125 mol) of 4N methylate and 20.7 g of l-chloro-2,3-propanediol are added. Stir at 60 ° C for 4 hours. The mineral salts are filtered off. Ethylene glycol was distilled off in vacuo.

After distillation, the residue is dissolved in 800 ml of 10N hydrochloric acid and stirred overnight at ambient temperature. The reaction mixture is evaporated to dryness and dissolved in 300 ml of ethanol. The mineral salts are filtered off. Ethanol is distilled under vacuum to isopropyl alcohol.

and the residue is crystallized from 11 The precipitate is filtered off and purified by high performance liquid chromatography (RP 18) (eluent water).

The overall yield after alkylation, deprotection and purification is 52%.

1) Thin layer chromatography on silica (60 F 254): methylene chloride / methanol 7/3, Rf 0.4.

2) High pressure liquid chromatography

Hypersil C8 5 mk 15 cm

Buffer solution NaH ₂ PO ₄ 0.01M 97 methanol 3

Purity 97%.

3) Iodine content,%: found 45.8%, theoretical 46.4%.

4) NMR (dimethylsulfoxide)

Broad, poorly resolved peak having center at 3.5 da.d., (18H); wide peak having center 4.5 m.d.

(OH) exchangeable with D ₂ O (6H); broadened to 8.4 md (NH) exchanged with D ₂ O (2H).

The product obtained does not have a characteristic melting point but has a zone of thermal decomposition.

EXAMPLE

Preparation of 5- [3-oxy-2- (oxymethyl) -propionamide] -N, N'-dimethylN, N'-bis (2,3-dioxypropyl) -2,4,6-triiodoisophthalamide.

a) Preparation of [2-isopropyl-1,3-dioxan-5-carboxamide] -N, N'-dimethyl-Ν, Ν'-bis- (2,3-dioxypropyl) -2,4,6-triiodoisophthalamide.

g (98 mmol) of 5- [2-isopropyl-1,3-dioxan-5-carboxamide] -2,4,6-triiodoisophthaloyl dichloride from Example 1a is suspended in 300 ml of isopropanol containing 41 ml (294 mmol) of triethylamine. . 31 g (295 mmol) of N-methylaminopropane-2,3-diol are added dropwise. Mix for 12 hours at ambient temperature. The triethylamine hydrochloride is filtered off.

The filtrate is evaporated to dryness, washed with water and eluted through a resin OH 'IRA 67.

After evaporation, the product is purified by passing through silanized silica (Kieselgel 60 Merk) using water as eluent.

Evaporation to dryness yielded 60 g of a white powder, yield 68.5%.

Iodine content: 96.4%

Purity by HPLC: 97%

Hypersil C8 25 cm mk

NaH ₂ PO ₄ 0.01 M Methanol

Thin layer chromatography:

SiO ₂ , Rf 0.12

0.25

0.30 0.36

Eluent CHC1 ₃ 55, MeOH 30, NH ₃

H ₂ O 10.

NMR Spectrum (DMSO) ^λ H 200 MHz, δ, md:

0, 9 / d (CH ₃ / 6H); 2.8 (s) N-CH3 ₍ 3H); 3 / s (N-CH ₃ / 3H); 3.3 (m / NCH ₂ and CH / 5H); 3.5-3.9 / spread signal / CH ₂ and CH / 8H /; 4.3 (kv / CH / 3H); 4.6 (t / OH / 2H); 4.7 (d / OH / 2H); 10.2 / broad signal / NH / lH /.

b) Preparation of 5- [3-oxy-2- (oxymethyl) -propionamide] -N, N'-dimethyl-N, N'-bis- [2,3-dioxypropyl] -2,4,6-triiodoisophthalamide.

g / 50.6 mmol / compound of step a) was dissolved in 101 mL of 5N hydrochloric acid. Mix for 12 hours at ambient temperature. The solution is then filtered and evaporated to dryness. The resulting solid is taken up in 100 ml of ethyl ether, then filtered and passed through silanized silica / Kieselguhr 60

Merk / eluting with water. 38 g of white powder are dried to dryness. Yield 90%.

The iodine content is 98.3%.

Purity by HPLC: 98%

Hypersil C8 25 cm mk io

NaH ₂ PO ₄ 0.01 M

Methanol

Thin layer chromatography

SiO ₂ , Rf

0.56 0, 63 0, 67

Eluent CHC1 ₃ 55, MeOH 30, NH ₃ H ₂ O 10.

NMR Spectrum / DMSO / 1H 200 MHz, δ, ppm:

2.7 / array / CH / IH / 2, 85 / F / s / N-CH ₃ / 3H /; 3.08 / unresolved d / N-CH ₃ / 3H /; 3.10-3.35 / m / N-CH ₂ ; 3.45 / kv / CH ₂ /

4H); 3.6-4 spread signal / OH / 6H /; 9.9 / spread signal / NH / lH /.

EXAMPLE.

5- [3-oxy-2 (oxymethyl) -N- (2,3-dioxypropyl) -propionamido] -N ', N' '- dimethyl-N', N '' - bis (2-oxyethyl) -2, Preparation of 4,6-triiodo-isophthalamide.

a) Preparation of 5- [2-isopropyl-1,3-dioxan-5-carboxamide] -Ν ', N' 'bis (2-oxyethyl) -2,4,6-triiodoisophthalamide.

0.126 mol of the product obtained according to the procedure of Example 1a, step a) were suspended in 400 ml of isopropanol containing 53 ml (0.378 mol) of triethylamine. 28.5 g (0.378 mol) of N-methylaminoethanol are added dropwise. The mixture was stored at room temperature for 16 hours.

The tretylamine hydrochloride was removed by filtration.

The filtrate was evaporated to dryness and washed with water, 2 x 500 ml. The precipitate was washed with 600 ml of isopropanol and filtered through activated carbon.

The filtrate was concentrated to dryness and washed with 600 mL of ethyl ether.

The precipitate was filtered off and dried in vacuo, 87% yield.

97% purity after high performance liquid chromatography.

TLC: SiO ₂ , eluent: CH ₂ Cl ₂ : 9, methanol: 1, Rf: 0.37, 0.33, 0.27.

b) 5- [3-Oxy-2 (oxymethyl) -N- (2,3-dioxypropyl) -propionamido] -N ', N' '- dimethyl-2', N '' - bis (2-oxyethyl) - Preparation of 2,4,6-triiodoisophthalamide.

To 20 g (0.0241 mol) of the product of step a), a

of the suspension is added dropwise 80 ml of monoglyme to 25.3 g (0.145 mol) of 30.8% w / w sodium methylate at 35 ° C. The mixture is maintained at this temperature for 1 hour. Then 16 g of l-chloro-2,3-propanediol (0.145 mol) are added dropwise. The mixture is kept at 35 ° C for 24 hours.

The mineral salts are filtered off. The monoglimus is evaporated in vacuo. The residue was taken up in 100 mL of 5N HCl and stirred at room temperature overnight. The reaction mixture is then concentrated to dryness. The oily residue is purified by high performance liquid preparative chromatography (RP 18 elution with water followed by water / methanol).

HPLC 95% hypersil CB 25 cm 5 mk

NaH ₂ PO ₄ 0.01 molar methanol 1 ml / m

Thin layer chromatography on SiO ₂ , Rf

0.16

0.28

0.21

0.36

Eluent - water, acetic acid, butanol 25/11/5.

Nuclear magnetic resonance spectrum NMR 5 dimethyl sulfoxide (DMSO) ^{χ Η 13} 0200 MHz, consistent with the expected structure.

Comparative tests of new compounds with Jonversol show their stability in aqueous solution.

Experimental Conditions Fractured Product% _1 EXAMPLE 2 JONVERSOL

25 ° C, pH 9, 3 months. 1.4 0 2.7

50 ° C, pH 9, 3 months. 2.5 1.5 20.5

Claims (1)

DEFINITION OF INVENTION Triiodobenzene compounds of formula I: Ri CH - CHa OH I CHaOH in which R _x represents monohydroxy-C ₁ -C ₄ alkyl, dihydroxy-C ₁ -C ₄ alkyl, R ₂ represents hydrogen or C ₁ -C ₄ alkyl; R ₃ represents hydrogen, monohydroxy-C ₁ -C ₄ alkyl or dihydroxy-C ₁ -C ₄ alkyl, method of obtaining, characterized in that: a) an amine of the formula (II) COC1 J - If N - ior ^{1 (II)} -LX ^> L-COC1 J acilina with chlorohydride, of the formula RCOC1 (III), to form a compound of formula (IV) (IV) ch ₂ oh / where R stands for CH, \ CH ₂ OH wherein the hydroxyl groups are protected; b) the resulting compound of formula (IV) with an amine of formula HN-R! (V), And _{2 to} form a compound of formula (VI) Rl J CO-N-Ri I Ra (VI) wherein R - R ₂ have the above meanings and then optionally alkylating the compound of formula VI with an alkylating agent R ₄ 'Z where R ₄ ' = R ₃ other than hydrogen, Z represents chlorine, in the presence of sodium methylate base, and further deprotects the -CH (CH ₂ OH) _{2 protecting} group.