Preparation of tri-iodo benzene compounds

Details Preparation of tri-iodo benzene compounds Preparation of tri-iodo benzene compounds

1999-11-12

2001-08-14

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S450000, C562S456000, C564S156000

Reexamination Certificate

active

06274762

ABSTRACT:

The invention relates to processes for the preparation of iodinated X-ray contrast agents and in particular key intermediates therefor, especially 2,4,6-triiodo-5-amino-N,N′-bis(2,3-dihydroxypropyl)-isophthalamide.
The use in X-ray imaging, eg. CT imaging, of iodinated compounds as contrast agents is well established. Such compounds generally contain one or two triiodinated benzene rings and examples of such compounds include iohexol, iopentol, iodixanol, iopamidol and ioversol. The compounds containing a single iodinated benzene ring are commonly referred to as monomers whereas those containing two iodinated benzene rings are referred to as dimers.
In order that the iodinated contrast agents should be water-soluble, the benzene ring is further substituted by solubilizing groups, eg. carboxyl groups, hydroxylated N or C substituted amide groups, or hydroxyalkyl groups.
The industrial manufacture of these iodinated contrast agents involves production of the chemical drug substance followed by formulation to the drug product. The drug substance is usually made in a multistep synthesis and then thoroughly purified before the formulation. In each synthetic step it is important to optimize the yield and minimize the production of impurities and in steps in which expensive reagents are used it is particularly important to optimize usage of those reagents. The iodination reagents are expensive and thus the triiodination of the aromatic ring is an important step which is generally performed at a late stage in the overall synthesis. In this step it is especially important to obtain a high yield with few impurities and minimal wastage of the iodination agent.
For several iodinated contrast agents the iodination step involves reaction of a 2,4,6-unsubstituted 5-amino-benzoic acid or derivative thereof (a “5-AB”) with an iododichloride salt, eg. sodium iodine chloride (NaICl
2
), in an aqueous medium to produce a 2,4,6-triiodo-5-AB.
In accordance with U.S. Pat. No. 3,145,197 (Hoey), the 5-AB is typically triiodinated by reaction with a significant excess of an iododichloride salt in an aqueous hydrochloric acid solution. In this procedure, the 5-AB is charged into the aqueous reaction medium and the iodinating agent is then added in one or two batches.
In WO89/09766 and WO91/01296 (Mallinckrodt) has described an iodination process in which a pre-prepared solution of an AB and a pre-prepared solution of an iodinating agent should be simultaneously added to a hot (74-85° C.) reaction medium in portions spread over a period of hours. In the processes described, there are over twelve additions of portions of the 5-AB and iodinating agent solutions.
The Mallinckrodt patent applications thus essentially teach away from any gradual addition of the iodinating agent to the 5-AB and teach instead that 5-AB and iodinating agent should together be gradually added to the reaction mixture.
We have now found that wastage of the iodinating agent can be reduced, yield of the triiodinated-AB can be optimized and a low impurity profile, particularly in relation to the azo compounds of the triiodinated product, can be obtained if the iodinating agent is added in two or more portions to a reaction medium containing the AB and the temperature of the reaction medium is changed, and preferably increased, during the iodination.
Thus the invention provides a process for the preparation of a compound containing a 2,4,6-triiodinated benzene ring, said process comprising reacting a 2,4,6-unsubstituted 5-amino-benzoic acid or derivative thereof with an iodine halide iodinating agent in an aqueous reaction medium, characterised in that the iodinating agent is added to an aqueous medium containing the 5-amino-benzoic acid or derivative at two different temperature ranges: (A) one or more primary portions of the agent are added at a temperature in the range 40 to 70° C. and then one or more secondary portions of the agent are added at a temperature in the range 75 to 95° C. or (B) one or more primary portions of the agent are added at a temperature in the range 75 to 95° C. and then one or more secondary portions of the agent are added at a temperature of 60 to 70° C.
Process variant (A) is generally preferred, with the iodinating agent used first at the lower temperature and then at the higher temperature. It is also preferred that at least two portions of the agent are added in the first (primary) addition stage, although a single portion may be used if desired. Thus the iodinating agent is preferably added in at least two primary portions to an aqueous medium containing the 5-amino-benzoic acid or derivative at a temperature in the range 40 to 70° C., in that the temperature of the aqueous medium is raised to within the range 75 to 95° C. and in that said iodinating agent is added in at least one secondary portion to the reaction medium while the reaction medium is at a temperature in the range 75 to 95° C. The invention will mainly be described in detail below with regard to this preferred process.
The 5-AB used in the process of the invention is preferably a 5-amino-benzamide, particularly preferably a 5-amino-benzamide which is alkylated at the amide nitrogen, preferably by a C
1-6
straight chain or branched alkyl group, particularly a hydroxylated alkyl group, eg. a group containing up to 6 hydroxyl groups especially a group containing 2, 3 or 4 hydroxyl groups, eg. a 2-hydroxyethyl, 2,3-dihydroxypropyl, 1,3-dihydroxyprop-2-yl, hydroxymethyl, 1,3-dihydroxy-2 hydroxymethyl-prop-2-yl, 2,3,4-trihydroxybutyl or 1,3,4-trihydroxybut-2-yl group. More particularly preferably the 5-AB is a 5-amino-isophthalamide and especially preferably both amide nitrogens are substituted as discussed above for the benzamide amide nitrogen. Alternatively the 5-AB used may be a 5-amino-N-alkyl-isophthalamic acid or a salt or ester thereof, preferably a compound in which the N-alkyl group is as discussed above for the 5-amino-benzamides.
Especially preferably the 5-AB is 5-amino-N,N′bis(2,3-dihydroxypropyl)-isophthalamide, a key intermediate in the production of iohexol as described in SE 7706792-4 (Nyegaard).
The 5-AB is preferably used in an initial concentration of 0.10 to 0.27 kg/L especially 0.18 to 0.25 kg/L, more especially 0.20 to 0.23 kg/L.
The iodine halide iodinating agent used in the process of the invention is iodine chloride or another iodine halide. This may be produced by adding molecular iodine and another molecular halogen to an alkali metal halide solution, eg. adding I
2
and Cl
2
to a NaCl or KCl solution. Preparation of KICl
2
and NaICl
2
in this way is a well established procedure. In the discussion below, iodine chloride will generally be referred to since this is the preferred iodine halide. Nonetheless other iodine halides may be used and the discussion is equally applicable to such other iodine halides.
In the process of the invention, the portions of iodine chloride are preferably 30 to 55% w/w, especially preferably 45-52% w/w, particularly about 50% w/w aqueous solutions, the percentages referring to ICl content. The portions may have different concentrations but conveniently all will have substantially the same ICI concentration, preferably about 50% w/w.
In the preferred method of carrying out the process, the primary portions will preferably be 2 to 6, more preferably 3, portions in total. After the first portion, which preferably corresponds to 1.0 to 2.5 equivalents, particularly 1.1 to 2.0 equivalents and especially 1.2 to 1.45 equivalents, of the 5-AB, the subsequent primary portions are preferably added when the remaining quantity of iodine chloride in the reaction mixture is in the range 0.05 to 1.0% w/w, preferably 0.075 to 0.5% w/w and especially 0.1 to 0.4% w/w. Subsequent primary portions preferably contain approximately equal quantities of iodine chloride. The total iodine chloride addition in the primary portions is preferably 2.05 to 2.85, more preferably 2.3 to 2.8, equivalents of the initial 5-AB. By one equivalent is meant a molar ratio of 1:3 of iodine chloride to iodinatio

Affiliated with

Also associated with

Rating

Preparation of tri-iodo benzene compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Preparation of tri-iodo benzene compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of tri-iodo benzene compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2491501