METHOD FOR THE ONE-POT PRODUCTION OF ORGANO-IODINATED COMPOUNDS

Abstract

The present invention concerns a process for the preparation of organo-iodized compounds, as well as their preparation intermediates. More particularly, the present invention concerns a process for the preparation of organo-iodized compounds which can be used as preparation intermediates in the synthesis of iodized contrast agents.

Claims

1-9. (canceled)

10. A process for preparing an organo-iodized compound, the process comprising the following steps: a) acylating 2,4,6-triiodo-5-aminoisophthalic acid having a chemical structure corresponding to formula (A): ##STR00038## with a compound having a chemical structure corresponding to formula (II):
R.sub.2C(O)Cl(II) to form an intermediate compound Y; b) chlorinating the intermediate compound Y to form the organo-iodized compound, which has a chemical structure corresponding to formula (I): ##STR00039## wherein: R.sub.1 is H or a methyl group; and R.sub.2 is selected from the group consisting of: (C.sub.1-C.sub.20)alkyl, linear or branched; (C.sub.1-C.sub.20)alkenyl, linear or branched; (C.sub.1-C.sub.20)alkynyl, linear or branched; (C.sub.3-C.sub.10)cycloalkyl; (C.sub.6-C.sub.10)aryl; a heterocyclyl comprising 3 to 10 atoms; and a heteroaryl comprising 6 to 10 atoms; wherein: said alkyl, alkenyl and/or alkynyl groups optionally being substituted with one or more substituent(s) selected from the group constituted by atoms of halogen, oxygen and nitrogen; said alkyl, alkenyl and/or alkynyl groups optionally being interrupted by one or more group(s) selected from the group constituted by O, C(O)O and OC(O); and said cycloalkyl, heterocyclyl, aryl and/or heteroaryl groups optionally being substituted with one or more substituent(s) selected from the group constituted by (C.sub.1-C.sub.20)alkyl, which may be linear or branched, and atoms of halogen, oxygen and nitrogen; wherein the steps a) and b) are performed without isolating the intermediate compound Y.

11. The process of claim 10, wherein the steps a) and b) are carried out in a single reactor.

12. The process of claim 10, wherein R.sub.2 is selected from the group consisting of: ##STR00040##

13. The process of claim 10, wherein steps a) and b) are carried out in the presence of a solvent selected from the group consisting of dimethylacetamide, propylene carbonate, acetonitrile, tetrahydrofuran, and mixtures thereof.

14. The process of claim 10, wherein step b) is carried out in the presence of a chlorination agent selected from the group consisting of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, phosphorus pentachloride, and methanoyl dichloride.

15. The process of claim 10, wherein the intermediate compound (Y) has a chemical structure corresponding to formula (Y1): ##STR00041## wherein: R.sub.1 is a methyl group; and R.sub.2 is selected from the group consisting of: (C.sub.1-C.sub.20)alkyl, linear or branched; (C.sub.1-C.sub.20)alkenyl, linear or branched; (C.sub.1-C.sub.20)alkynyl, linear or branched; (C.sub.3-C.sub.10)cycloalkyl; (C.sub.6-C.sub.10)aryl; a heterocyclyl comprising 3 to 10 atoms; and a heteroaryl comprising 6 to 10 atoms; wherein: said alkyl, alkenyl and/or alkynyl groups optionally being substituted with one or more substituent(s) selected from the group constituted by atoms of halogen, oxygen and nitrogen; said alkyl, alkenyl and/or alkynyl groups optionally being interrupted by one or more group(s) selected from the group constituted by O, C(O)O and OC(O); and said cycloalkyl, heterocyclyl, aryl and/or heteroaryl groups optionally being substituted with one or more substituent(s) selected from the group constituted by (C.sub.1-C.sub.20)alkyl, which may be linear or branched, and atoms of halogen, oxygen and nitrogen; and wherein R.sub.2 is not ##STR00042##

16. The process of claim 10, wherein the intermediate compound (Y) has a chemical structure corresponding to formula (ay), formula (cy), or formula (ey) as depicted below: ##STR00043##

17. A compound having a chemical structure corresponding to formula (Y1): ##STR00044## wherein: R.sub.1 is a methyl group; and R.sub.2 is selected from the group consisting of: (C.sub.1-C.sub.20)alkyl, linear or branched; (C.sub.1-C.sub.20)alkenyl, linear or branched; (C.sub.1-C.sub.20)alkynyl, linear or branched; (C.sub.3-C.sub.10)cycloalkyl; (C.sub.6-C.sub.10)aryl; a heterocyclyl comprising 3 to 10 atoms; and a heteroaryl comprising 6 to 10 atoms; wherein: said alkyl, alkenyl and/or alkynyl groups optionally being substituted with one or more substituent(s) selected from the group constituted by atoms of halogen, oxygen and nitrogen; said alkyl, alkenyl and/or alkynyl groups optionally being interrupted by one or more group(s) selected from the group constituted by O, C(O)O and OC(O); and said cycloalkyl, heterocyclyl, aryl and/or heteroaryl groups optionally being substituted with one or more substituent(s) selected from the group constituted by (C.sub.1-C.sub.20)alkyl, which may be linear or branched, and atoms of halogen, oxygen and nitrogen; and wherein R.sub.2 is not ##STR00045##

18. A compound having a chemical structure corresponding to formula (ay), formula (cy), or formula (ey) as depicted below: ##STR00046##

Description

EXAMPLES

Analytical Methods Used

[0115] The synthesis compounds were analysed using two Nuclear Magnetic Resonance techniques: proton NMR at 400 MHz and carbon-13 NMR at 100 MHz. The compounds were dissolved in DMSO-d6. The compounds were also analysed by Mass Spectrometry, in negative mode and in positive mode. The NMR identification was carried out using a 400 MHz NMR spectrometer from Bruker. The MS identification was carried out using a Thermo Fischer Q-Exactive Orbitrap type mass spectrometer.

[0116] The term V is intended to designate a volume ratio, i.e. the volume of a reagent or a solvent with respect to 1 kg of AATI.

[0117] The term eq is intended to designate a number for a molar equivalent, i.e. the ratio between the number of moles of a reagent and the number of moles of AATI.

Example 1: Synthesis of 5-[[[2-(1-methylethyl)-1,3-dioxan-5-yl]carbonyl]amino-2,4,6-triiodo-1,3-benzenedicarbonyl dichloride (DICOA)

[0118] ##STR00033##

Operating Method 1:

Acylation Step:

[0119] Dimethylacetamide (33.7 mL; 1.35 V) and 2-(1-methylethyl)-1,3-dioxane-5-carboxylic acid (8.7 g, 1.125 eq) were mixed at 25 C. until the starting acid had dissolved. The reaction medium was cooled to 0 C., then thionyl chloride (6.31 g, 1.06 eq/starting acid) was added over 1 h-1 h 30 between 0 C. and 15 C. The medium was stirred for 3 h at 15 C. in order to complete the reaction. Propylene carbonate (3.7 mL, 0.15 V) was added to a 250 mL reactor at 15 C.

[0120] Next, 5-amino-2,4,6-triiodoisophthalic acid (25 g; 1 eq) was introduced over 30 minutes. When introduction was complete, the medium was heated up to a temperature of 18 C., then the acylation reaction was carried out over a period of 24 hours at a temperature in the range 18 C. to 30 C.

[0121] The intermediate 5-[[[2-(1-methylethyl)-1,3-dioxan-5-yl]carbonyl]amino]-2,4,6-triiodo-1,3-benzenedicarboxylic acid (compound (ay)) was then formed.

[0122] The medium was then fluidified with propylene carbonate (25 mL; volume ratio of 1), then cooled to a temperature of 5 C.

Chlorination Step:

[0123] As soon as the medium had reached a temperature of 5 C., thionyl chloride (18 g; equivalent molar ratio of 3.5) was added. The thionyl chloride addition lasted 2 hours at a temperature of 5 C. When introduction of the reagent was complete, the chlorination reaction was carried out over a period of 5 hours at a temperature of 5 C.

[0124] The degree of conversion thus obtained was 85% (s/s) of 5-[[[2-(1-methylethyl)-1,3-dioxan-5-yl]carbonyl]amino]-2,4,6-triiodo-1,3 benzenedicarbonyl dichloride.

[0125] The reaction medium was slowly added to a mixture of water/ethanol/sodium acetate. The solid obtained was filtered, washed, dried then analysed.

[0126] The yield obtained was 82%.

Analytical Results:

Nuclear Magnetic Resonance:

[0127] .sup.1H NMR (400 MHz, DMSO-d6) : 10.4 (s, 1H), 4.3 (d, J=4.9 Hz, 1H), 4.3 (m, 2H), 3.9 (t, J=11.4 Hz, 2H), 3.0 (ddt, J=11.1, 6.9, 4.6 Hz, 1H), 1.7 (dhept, J=6.9, 4.8 Hz, 1H), 0.9 (d, J=6.8 Hz, 6H).

[0128] .sup.13C NMR (101 MHz, DMSO-d6) : 169.4-169.8, 168.3, 149.7-150.3, 143.1-143.9, 105.0, 87.1-102.0, 69.0, 41.9, 32.5, 17.3.

Mass Spectrometry:

[0129] [MH].sup.=749.7321 uma (exact mass=749.7310 uma)

[0130] [M+H].sup.+=751.7453 uma (exact mass=751.7456 uma)

Operating Method 2:

Acylation Step:

[0131] Dimethylacetamide (40 mL; 1.6 V) and 2-(1-methylethyl)-1,3-dioxane-5-carboxylic acid (10.2 g, 1.3 eq) were introduced into a reactor with a volume of 250 mL. The reaction medium was cooled to 0 C., then thionyl chloride (5.4 g 1.06 eq/starting acid) was added over 1 h-1 h 30 at between 0 C. and 15 C. The medium was stirred for 3 h at 15 C. in order to complete the reaction. Next, 5-amino-2,4,6-triiodoisophthalic acid (25 g, 1 eq) was introduced over 30 minutes.

[0132] When introduction was complete, the medium was heated up to a temperature of 18 C., then the acylation reaction was carried out over a period of 70 hours at a temperature of 18 C.

[0133] The intermediate 5-[[[2-(1-methylethyl)-1,3-dioxan-5-yl]carbonyl]amino]-2,4,6-triiodo-1,3-benzenedicarboxylic acid (compound (ay)) was then formed.

Chlorination Step:

[0134] The reaction medium was then cooled to a temperature of 10 C. As soon as the medium had reached a temperature of 10 C., thionyl chloride (26.6 g, 5 eq) was added. The thionyl chloride addition lasted 2 hours, at a temperature of 10 C. When introduction of the reagent was complete, the chlorination reaction was carried out over a period of 12 hours at a temperature of 10 C.

[0135] The degree of conversion thus obtained was 86% (s/s) of 5-[[[2-(1-methylethyl)-1,3-dioxan-5-yl]carbonyl]amino]-2,4,6-triiodo-1,3-benzenedicarbonyl dichloride.

[0136] The reaction medium was then slowly added to a mixture of water/ethanol/sodium acetate. The solid obtained was filtered, washed, dried then analysed.

[0137] The yield obtained was 84.5%

Analytical Results:

Nuclear Magnetic Resonance:

[0138] .sup.1H NMR (400 MHz, DMSO-d6) : 10.4 (s, 1H), 4.3 (d, J=4.9 Hz, 1H), 4.3 (m, 2H), 3.9 (t, J=11.4 Hz, 2H), 3.0 (ddt, J=11.1, 6.9, 4.6 Hz, 1H), 1.7 (dhept, J=6.9, 4.8 Hz, 1H), 0.9 (d, J=6.8 Hz, 6H),

[0139] .sup.13C NMR (101 MHz, DMSO-d6) : 169.4-169.8, 168.3, 149.7-150.3, 143.1-143.9, 105.0, 87.1-102.0, 69.0, 41.9, 32.5, 17.3.

Mass Spectrometry:

[0140] [MH].sup.=749.7321 uma (exact mass=749.7310 uma)

[0141] [M+H].sup.+=751.7453 uma (exact mass=751.7456 uma)

Example 2: Synthesis of 5-(acetylamino)-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride (Intermediate in the Synthesis of Iohexol/Iodixanol)

[0142] ##STR00034##

Acylation Step:

[0143] Dimethylacetamide (67.5 mL; 1.35 V) and propylene carbonate (7.5 mL; 0.15 V) were mixed in a reactor with a volume of 250 mL.

[0144] Acetyl chloride (7.7 g; 1.1 eq) was then added to the mixture. After cooling to a temperature of 15 C., 5-amino-2,4,6-triiodoisophthalic acid (50 g; 1 eq) was introduced over 30 minutes. When introduction was complete, the medium was heated up to a temperature of 18 C., then the acylation reaction was carried out over a period of 36 hours at a temperature of 18 C.

[0145] The intermediate 5-(acetylamino)-2,4,6-thiodobenzene-1,3-dicarboxylic acid (compound (dy)) was then formed.

[0146] The medium was then fluidified with dimethylacetamide (50 mL; 1 V) and propylene carbonate (50 mL; 1 V). Next, the medium was cooled to a temperature of 5 C.

Chlorination Step:

[0147] As soon as the medium had reached a temperature of 5 C., thionyl chloride (52.8 g; 5 eq) was added. The thionyl chloride addition lasted 2 hours at a temperature of 5 C. When introduction of the reagent was complete, the chlorination reaction was carried out over a period of 5 hours at a temperature of 5 C.

[0148] The degree of conversion thus obtained was 85% (s/s) of 5-(acetylamino)-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride.

[0149] The reaction medium was slowly added to a mixture of water/ethanol/sodium acetate. The solid obtained was filtered, washed, dried then analysed.

[0150] The yield obtained was 60%.

Analytical Results:

Nuclear Magnetic Resonance:

[0151] .sup.1H NMR (400 MHz, DMSO-d6) : 10.1 (s, 1H), 2.1 (s, 3H).

[0152] .sup.13C NMR (101 MHz, DMSO-d6) : 168.3, 144.1-150.2, 86.8-102.2, 169.5-169.8, 144.8, 23.4.

Mass Spectrometry:

[0153] [MH].sup.=635.6634 uma (exact mass=635.6630 uma)

[0154] [M+Na].sup.+=659.6593 uma (exact mass=659.6594 uma)

Example 3: Synthesis of 5-{[(2S)-2-(acetyloxy)-1-oxopropyl}amino-2,4,6-triiodo-1,3-benzenedicarbonyl dichloride (Intermediate in the Synthesis of Iopamidol)

[0155] ##STR00035##

Acylation Step:

[0156] Dimethylacetamide (34 mL; 1.35 V) and propylene carbonate (3.75 mL; 0.15 V) were mixed in a reactor with a volume of 250 mL.

[0157] (2S)-1-chloro-1-oxopropan-2-yl acetate (7.5 g; 1.1 eq) was then added to the mixture. After cooling to a temperature of 15 C., 5-amino-2,4,6-triiodoisophthalic acid (25 grams; 1 eq) was introduced over 30 minutes. When introduction was complete, the medium was heated up to a temperature of 18 C., then the acylation reaction was carried out over a period of 66 hours at a temperature of 18 C.

[0158] The intermediate 5-{[(2S)-2-(acetyloxy)-1-oxopropyl}amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid (compound (ey)) was then formed.

[0159] The medium was then diluted with propylene carbonate (25 mL, 1 V). Next, the medium was cooled to a temperature of 5 C.

Chlorination Step:

[0160] As soon as the medium had reached a temperature of 5 C., thionyl chloride (18.5 g; 3.5 eq) was added. The thionyl chloride addition lasted 1 hour at a temperature of 5 C. When introduction of the reagent was complete, the chlorination reaction was carried out over a period of 5 hours at a temperature of 5 C.

[0161] The degree of conversion thus obtained was 87% (s/s) of 5-{[(2S)-2-(acetyloxy)-1-oxopropyl}amino-2,4,6-triiodo-1,3-benzendicarbonyl dichloride.

[0162] The reaction medium was slowly added to a mixture of water/ethanol/sodium acetate. The solid obtained was filtered, washed, dried then analysed.

[0163] The yield obtained was 70%.

Analytical Results:

Nuclear Magnetic Resonance:

[0164] .sup.1H NMR (400 MHz, DMSO-d6) : 10.3 (s, 1H), 5.2 (q, J=6.9 Hz, 1H), 2.1 (s, 3H), 1.5 (d, J=6.9 Hz, 3H).

[0165] .sup.13C NMR (101 MHz, DMSO-d6) : 142.9-150.4, 87.2-101.9, 168.5-170.0, 169.9, 168.9, 69.9, 21.3, 18.0.

Mass Spectrometry:

[0166] [MH].sup.=707.6847 uma (exact mass=707.6841 uma)

[0167] [M+Na].sup.+=731.6806 uma (exact mass=731.6806 uma)

Example 4: Synthesis of 5-{[(acetyloxy)acetyl]amino}-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride (Intermediate in the Synthesis of Ioversol)

[0168] ##STR00036##

Acylation Step:

[0169] Dimethylacetamide (67.5 mL, 1.35 V) and propylene carbonate (7.5 mL; 0.15 V) were mixed in a reactor with a volume of 250 mL.

[0170] 2-chloro-2-oxoethyl acetate (13.3 g; 1.1 eq) was then added to the mixture. After cooling to a temperature of 15 C., 5-amino-2,4,6-triiodoisophthalic acid (50 g; 1 eq) was introduced over 45 minutes. When introduction was complete, the medium was heated up to a temperature of 18 C., then the acylation reaction was carried out over a period of 65 hours at a temperature of 18 C.

[0171] The intermediate 5-{[(acetyloxy)acetyl]amino}-2,4,6-triiodobenzene-1,3-dicarboxylic acid (compound (cy)) was then formed.

[0172] The medium was then diluted with propylene carbonate (50 mL; 1 V). Next, the medium was cooled to a temperature of 5 C.

Chlorination Step:

[0173] As soon as the medium had reached a temperature of 5 C., thionyl chloride (37 g; 3.5 eq) was added. The thionyl chloride addition lasted 2 hours at a temperature of 5 C. When introduction of the reagent was complete, the chlorination reaction was carried out over a period of 4 hours at a temperature of 5 C.

[0174] The degree of conversion thus obtained was 90.5% (s/s) of 5-{[(acetyloxy)acetyl]amino}-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride.

[0175] The reaction medium was slowly added to a mixture of water/ethanol/sodium acetate. The solid obtained was filtered, washed, dried then analysed. The yield obtained was 87%.

Analytical Results:

Nuclear Magnetic Resonance:

[0176] .sup.1H NMR (400 MHz, DMSO-d6) : 10.4 (s, 1H), 4.7 (s, 2H), 2.2 (s, 3H).

[0177] .sup.13C NMR (101 MHz, DMSO-d6) : 143.0-150.3, 87.3-102.0, 169.4-169.8, 170.1, 166.1, 62.6, 21.0.

Mass Spectrometry:

[0178] [MH].sup.=693.6691 uma (exact mass=693.6684 uma)

[0179] [M+Na].sup.+=717.6645 uma (exact mass=717.6649 uma)

Example 5: Synthesis of 5-[(chloroacetyl)amino]-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride (Intermediate in the Synthesis of Ioversol)

[0180] ##STR00037##

Acylation Step:

[0181] Dimethylacetamide (67.5 mL; 1.35 V) and propylene carbonate (7.5 mL; 0.15 V) were mixed in a reactor with a volume of 250 mL.

[0182] Chloroacetyl chloride (11 g; 1.1 eq) was then added to the mixture. After cooling to a temperature of 15 C., 5-amino-2,4,6-triiodoisophthalic acid (50 g; 1 eq), was introduced in portions, i.e. approximately 3.4 g every two minutes, over 30 minutes. When introduction was complete, the medium was heated up to a temperature of 18 C., then the acylation reaction was carried out over a period of 40 hours at a temperature of 18 C.

[0183] The intermediate 5-[(chloroacetyl)amino]-2,4,6-triiodobenzene-1,3-dicarboxylic acid (compound (by)) was then formed.

[0184] The medium was then fluidified with dimethylacetamide (50 mL; 1 V) and propylene carbonate (50 mL; 1 V). Next, the medium was cooled to a temperature of 5 C.

Chlorination Step:

[0185] As soon as the medium had reached a temperature of 5 C., thionyl chloride (52.9 g; 5 eq) was added. The thionyl chloride addition lasted 3 hours at a temperature of 5 C. When introduction of the reagent was complete, the chlorination reaction was carried out over a period of 18 hours at a temperature of 5 C.

[0186] The degree of conversion thus obtained was 88% (s/s) of 5-[(chloroacetyl)amino]-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride.

[0187] The reaction medium was slowly added to a mixture of water/ethanol/sodium acetate. The solid obtained was filtered, washed, dried then analysed. The yield obtained was 86%.

Analytical Results:

Nuclear Magnetic Resonance

[0188] .sup.1H NMR (400 MHz, DMSO-d6) : 10.6 (s, 1H), 4.4 (s, 2H).

[0189] .sup.13C NMR (101 MHz, DMSO-d6) : 142.9-150.3, 87.5-101.8, 169.4-169.8, 164.8, 98.4, 43.3.

Mass Spectrometry:

[0190] [MH].sup.=669.6245 uma (exact mass=669.6240 uma)

[0191] [M+Na].sup.+=693.6202 uma (exact mass=693.6205 uma)