MXPA99007245A - Process for the preparation of iodinated contrast agents and intermediates therefor - Google Patents

Abstract

The invention provides a process for the production of a 2,3-dihydroxypropylamino compound, said process comprising the reaction steps of:(i) obtaining an allylamino compound;(ii) epoxidizing said allylamino compound to yield an epoxypropylamino compound;and (iii) hydrolysing said epoxypropylamino compound to yield a 2,3-dihydroxypropylamino compound. This process may be used to produce simple 2,3-dihydroxypropylamino compounds such as APD or complex ones such as BAPD (an intermediate in the production of iohexol).

Description

Process for the preparation of iodinated contrast agents and intermediate compounds thereof FIELD OF THE INVENTION This invention relates to a process for the preparation of iodinated raste agents for radiography; with the intermediates in the preparation of these contrast agents; and with processes for the preparation of these intermediate compounds.

BACKGROUND OF THE INVENTION Iodinated organic compounds, in particular the monomeric and dimeric compounds of triiodofenium, have a commercial use established for a long time and very widespread as contrast agents for radiography. Initially, commercially available compounds were ionic compounds (eg, metrizoate, iodipated ida, iodanida, iobenzamate, iocarmate, iocetamate, iodoxamate, ioglycate, ioglycolate, iopanoate, iofendylate, iopronate, ioserate, iota alato, iotroxato, ioxaglate and ioxi talama). , but more recently, the agents? Contrast for radiography, commercial, dominant, have been the nonionic compounds (such as iohexol, iopamidol, iomeprol, iopentol, iopromide, iosimida, iotasul, iotrolan, ioversol, metrizamide and iodixanol) that can be administered parenterally to REF .: 30987 higher concentrations and with reduced adverse effects. The nonionic compounds derive their necessary solubility in water from the presence, in their molecular structures, of non-ionic solubilizing groups such as the hydroxyalkyl groups. Thus, as an example, iohexol, iopentol and iodixanol have the monomeric and dimeric structures of triodopheni which incorporate the hydroxyalkyl solubilizing groups shown below: IODI.XANOL The preparation of these compounds involves the introduction of a 2, 3-dihydroxypropyl 1 amide group in the carbonyls attached to the ring. As described by Haavaldsen et al., In Acta Pharm Suec 2_0: 219-232 (1983), this is achieved by reacting 3-amino-1,2-propanediol (APD) with a carbonyl group attached to the ring. A similar reaction is discussed in US-A-4250113 (Nyegaard &Co.). Therefore, APD has been a critical reagent in the synthesis of commercial x-ray contrast agents of 2,3-dihydroxypropyl laminocarboni 1 -t riyodofeni 1 o. However, a major problem has arisen in producing APD of sufficiently high purity (e.g.,> 99.9%). A synthetic approach for the production of APD involves the reaction of glycidol (1-hydroxy-2,3-epoxypropane) with ammonia. This reaction is not only potentially explosive, but the product of the reaction is a mixture of APD and 2-amino-1,3-propanediol. Purification of the reaction product requires very difficult distillation because the difference between the boiling point of the two aminodiols is very small.

An alternative approach has been to epoxidize allyl chloride, hydrolyze it to produce 1-chloro-2,3-propanediol, and displace the chlorines with ammonia to give APD. However, the basic conditions used can lead to the epoxide being able to re-form with the reaction with ammonia which then produces a certain amount of the undesired 2-amino product. Again, therefore, difficult distillation is required to give the high purity APD.

A further approach has been to avoid the use of the epoxides together and generate the diol group directly from an allyl group by oxidation with osmium tetraoxide (see US-A-5191119 (Cook imaging)). However, this approach involves not only the use of osmium tetraoxide, but, as an intermediate, isophthaloyl chloride. The synthesis of isophthaloyl chloride is a reaction with a hostile environment and the use of osmium tetraoxide; highly poisonous, in one of the final preparations steps, for a product that will be injected into patients, is unacceptable.

BRIEF DESCRIPTION OF THE INVENTION It has been found that the compounds of 2,3-dihydroxypropyl 1 ami (as the APD) can be produced without contamination by the 2-amino by the epoxidation of an allylamine, followed by hydrolysis. In addition, the epoxidation and hydrolysis reactions can be carried out in an alkylamine rboni 1-phenyl compound or, which makes the use of APD in the preparation of contrast agents, such as iohexol, quite unnecessary.

Accordingly, viewed from one aspect, the invention provides a process for the production of a 2,3-dihydroxypropyl lactam compound, wherein this process comprises the reaction steps of: (i) obtaining an allylamino compound; (ii) epoxidizing the allylamino compound to produce an epoxyprop opium compound; and (iii) hydrolyzing the epoxypropyl 1-amino compound to give a 2,3-dihydroxy-1-amino compound. In the simplest form, the process of the invention may have an allylamine as the initial allylamine compound for step (i) and the APD as the 2,3-dihydr oxipr opy 1 amino product, from step (iii).

DETAILED DESCRIPTION OF THE INVENTION In order to enhance the rates or yields of the reaction, in the reaction process, it may be desirable to select as the initial allylamino compound an N-substituted compound or N, N-di-substituted, where the substituents they are selected to reduce the electron donor power of nitrogen. Preferably, the initial allylamino compound will have one or two N-acyl substituents. These substituents may be small (e.g., groups containing up to six carbons), or large (e.g., groups containing up to 50 carbons); and may be removed in the hydrolysis step (lii), or may be allowed to remain in the 2,3-dihydroxypropylamino product of step (iii).

Examples of suitable acyl groups include the alkylcarbonyl, arylcarbonyl, aralkyl 1 -carbonyl, carboxylcarbonyl, and aryl-1-carbonyl groups, in which any alkyl or alkylene group can be straight chain or branched; and in the alkyl or alkylene groups, any carbon skeleton which is not located adjacent to the carbon atom may be replaced by nitrogen or oxygen atoms; or to be substituted by the oxo, hydroxyl or other groups and in which the aryl groups are optionally substituted by, eg, nitro, halo (eg iodo) groups, the aminocarbonyl, alkynylaminocarbonyl, amino, alkylamino, and N -alkyl-acylamino. The aryl groups will preferably be carbocyclic groups with a ring of 6 to 10 atoms, and the alkyl, alkylene, alkenyl and acylamino groups will preferably contain up to 6 carbon atoms, e.g., methyl, ethyl, propyl, allyl, vinyl, acetamido, etc.

Accordingly, acyl groups include structures that are present in radiography contrast agents, such as iohexol or er. intermediates for these agents (e.g., pre-iodination compounds).

Preferred starting materials for step (i) of the process of the invention include N, N-bis-acylalkylamines (eg N, N-bi-sacacetyl-alkylamine) and 1,3-bi s (alkylamino-carbonyl) benzenes (eg 1, 3 -bi s (a 1 i 1 aminocarboni 1) - 5-nitro-benzene and 1,3-bis (alkylaminocarbonyl) -2,4-6,1-diisodo-5-nitro-benzene. N-bis-acetylallylamine can be prepared, for example, by treating allylamine with acetic anhydride, while the 1,3-bis (allylaminocarbonyl-1) -benzenes can be prepared, for example, by reacting the alkylamine with a diester of the isophthalic acid, eg the methyl diester.

Accordingly, as an example, reaction schemes 1 and 2, shown below, illustrate the use of the process of the invention for the preparation of simple structures such as APD and more complex structures such as bis (amide-1-propane-2). , 3-di ol) of 5-ni t ro-isof tal acid (BAPD), a key intermediate product for the production of iohexol. Indeed, BAPD is the intermediate compound that is produced in a conventional manner by means of the reaction of APD with 5-nitro-isophthalic acid or its dimethyl ester.

Scheme 1? C2? - - -NH2 -N < H) "(? E> 2_n (where n = 0 or 1) N (H CAc) 2.a (AK » Scheme 2 (unaEi The oxidation of the allyl group in the process of the invention can be carried out with a range of oxidizing systems and / or catalysts. Suitable oxidants include air, oxygen, hydrogen peroxide, hypochlorite, and organic peroxides such as metachlorophenic acid. Oxidants such as air, oxygen and hydrogen peroxide can be used to generate in situ a more effective oxidizing species - thus, for example, a mixture of hydrogen peroxide and acetic acid will generate the peracetic acid oxidant; For the catalyst, where it is used, a large number of metals and their compounds (e.g., oxides, complexes, etc.) can be used. Examples of suitable metal catalysts include Ti, V, Mn, Fe, Co, Mo, Ru, Rh, W, Re and Os (although OsO.i and Ru0 should not be used). For the examples of catalyst systems reference can be made to Venturello et al., J. Org. Chem. 53_: 1553-1557 (1988), Venturello et al. Synthesis, Communications 295-297 (April 1989), Palocki JACS 116: 9333-9334 (1994) and Bernadou JACS 116: 9375-9376 (1994). The selection of a catalyst will depend, to a large extent, on whether the diolamino product, by itself, is used as a contrast agent or is an intermediate of the final phase for a contrast agent. In these cases, the use of very toxic catalysts should be avoided.

The epoxypropyl 1 aminocarbonyl compounds, which can be produced using the process of the invention, e.g., the BAAE compound, are novel and form a further aspect of the invention. Similarly, the 5-NIPDA product is new and forms a further aspect of the invention Where the intended end product of the process of the invention is APD, because this is a small molecule that can be easily freed from the initial material and catalyst contamination by distillation, a direct 2,3-dihydroxylation of the starting compound can be carried out. of allylamine (eg allylamine, N-acetyl-allylamine or N, N-bis acetyl-allyl) using catalysts such as, for example, Os04 and Ru0. Accordingly, viewed from a further aspect, the invention provides a process for the preparation of APD, wherein the process comprises subjecting a 2, 3-bi-hydroxylation reaction to an optionally N-acylated allylamine or N, N-bi satiety. and, if required, hydrolyzing a reaction product of N-acyl or N, N-bisacyl-2,3-dihydroxyriphenyl amine.

In the process of the invention, the hydrolysis step (iii) can be carried out using conventional hydrolysis techniques, e.g., acid catalysis. The hydrolysis conditions can be selected to remove or leave any acyl substituent on the epoxypropyl amino nitrogen.

For the production of 2, 3-dihydroxypropylamino contrast agents for radiography, in particular non-ionic contrast agents containing a structural component of 1- (2, 3-dihydroxy propylamino-carboni 1) -2, 4, 6-iodo-phene 1 or, such as iohexol, iopenroi and iodixanol, the process of the invention may include one or more of the following steps of the process: (iv) iodine a compound of 2,3-dihydroxylamino diol -carbonylphenyl; (v) converting a phenyl group substituent, which is in a 2,3-dihydroxypropyl-1-aminocarbonylphenyl compound, into a solubilizing group, eg, a hydroxylated and / or alkoxylated group, for example, an alkylaminocarbonyl group or which 1 carboni lamino (optionally carrying an N-acyl substituent eg, CH; CO); and (vi) conjugate two 2,3-dihydroxypropyl-1-aminocarbonyl-1-phenyl compounds to produce a dimeric compound.

Thus, as described by Haavaldsen (supra), non-ionic contrast agents can be conveniently produced following a process scheme such as the following: < S) where the step iodination (D) is omitted if the iodization has been carried out before, eg, before the production of the initial product of the acid bis-ester of the 5-nitric acid or 1-ico acid (1), or the iodization has been done before steps (A), (B) or (C). (Haavaldsen (supra) suggested iodization before step (C)). The groups R in the esguema established above are not differentiated. The specific groups chosen would clearly depend on the desired final product. Thus, in the case of using the process of the invention to produce iohexol, step (A) will conveniently involve the reaction of 5-NIPDE with allylamine to produce 5-NI PDA; epoxidation until BAAE; and hydrolysis to produce BAPD, which is then reduced, acetylated, N-hydroxy to the side and iodinated.

The patents and other references mentioned herein are therefore incorporated by reference.

The invention will now be further described with reference to the following non-limiting examples. The initial, intermediate and final products were analyzed by HPLC and 1 JC NMR. The HPLC system used was based on absorption at 240 nm (where the benzene ring absorbs). The HPLC system was entirely Dionex glass; used a Supelcosil LC-18 DB column; used as eluent 72% methanol, 6.0 mM tetrabutylammonium bisulfate, 4.0 mM sodium hydroxide; had a flow rate of 1.0 mL / min and a sample volume of 25 μL; and used a UV detector at 240 nm. The HPLC retention times, in minutes, were established as shown, in Table 1 below: Table 1 Bis (amide-l-propane-2, 3-diol) of 5-nitro-isoftalic acid 2.87 (BAPD) I 2.87 N- (propane-2, 3-diol) -benzamide Bis (amide-l-propane-2, 3-diol) of 5-nitro-isoftalic acid 2.98 (BAPD) II Bis (allylamide epoxide) of 5- nitro-isophthalic 3.12 (BAAE) 3.30 N-allyl-benzamide epoxide 5-nitro-isophthalic acid 3.40 L-allylamide-3-allylamide epoxide of 5-nitro-3.48 isophthelic acid 3.58 N-allyl-benzamide Bis (allylamide) of 5-nitro-isoftalic acid (5-NIPDA) 4.05 M-chloroperbenzoic acid 4.50 M-chlorobenzoic acid .4-6.1 Dimethyl ester of 5-nitro-isophthalic acid (5-NIPDE) 6.25 It should be noted that (a) those retention times are reduced unless a freshly prepared eluent is used, and (b) the BAPD results in two peaks.

Table 2, below, shows the peak assignments of - * - 'C for the derivatives of 5-nitro-isophthalic acid, 5-NIPDA, BAAE and BAPD: -NIPDA BAAE BAPD E 163.6 164 .0 166.5 D 147.9 148 .0 148.0 A 134.8 135 .1 135.6 B 132.3 130 .7 132.1 C 124.2 124 .0 125.0 F 41.8 41. 0 43.1 G 136. O 44. 7 63.9 H 115.7 49. 8 70.8 Example 1 N-al i lbenzamide (NAB) was purchased from the Monomer-Polymer Laboratories. It was determined that it was 99.5% pure. Chromatography using chloroform and silica gel increased the purity of the NAB "" to 99.9%. 1.05 g of the purified NAB was treated with a solution of 2.14 g of m-chloroperbenzoic acid (MCPBA) in 15 mL of THF. After 64 hours at room temperature, HPLC showed no MCPBA remained. The conversion was 89.7% with 15.8% selectivity to (BAPD) and 78.7% selectivity to the epoxide of N-to-ilbenzamide.

Example 2 (Comparative) 23.9 g of the 5-nitro-isophthalic acid dimethyl ester were added to 60 mL of boiling methanol followed by 21.84 g of 1-amino-propane-2,3-diol (APD). A white solid formed. Another 100 mL of methanol was added and the mixture was heated over the weekend. The white product was filtered from the hot solution, then washed with a small amount of methanol and dried in a vacuum oven. The isolated yield of 5-nitro-isophthalic bis (amide-1-propane-2, 3-diol) (BAPD) was 19.5 g. They were identified by NMR of *? and of 13C.

EXAMPLE 3 Fifty grams of the 5-nitro-isophthalic acid dimethyl ester (5-NIPDE) was dissolved in 75 mL of methanol and 100 mL of allylamine. The solution was heated to reflux under nitrogen atmosphere for approximately ten hours. The TLC showed that the "conversion was complete, approximately one liter of a methanol / water mixture was added, the solution was heated and clarified at a temperature of 59 ° C. A little more water was added and the The temperature was increased to 75 ° C. The solution was allowed to cool slowly to room temperature with stirring The product was filtered and dried in a vacuum oven at 50 ° C. The product was dissolved in hot ethanol and slowly cooled to 4 ° C. C. Filtration followed by repeated drying gave 47.82 g of the product (79% yield) A second crop can be easily obtained from the remaining filtrates (total yield 94%) The material was identified by HPLC, NMR and MS as the bi s (al i 1 amide) of the 5-nitric acid of this co (5-NIPDA).

For example, 1.27 g of 5-NIPDA were dissolved in 15 mL of THF. It was determined that m-chloroperbenzoic acid (MCPBA) had a remaining 57% of its peroxide activity. 3.09 g of this material were added, representing an excess of 1.16 times of the peroxide on the allyl substituents. The reaction was stirred at room temperature and the HPLC showed 80% conversion in about six hours. The reaction was left overnight. The conversion to diepoxide (BAAE) was complete. The investigation included the addition of methylene chloride and water containing sodium carbonate or bicarbonate. The organic fractions were combined. Removal of the solvent gave 0.80 g of a glass. HPLC showed that the sample had a purity of 73%. Mass spectroscopy showed a peak corresponding to the addition of two oxygens, corresponding to the bis allyl epoxide (BAAE), which was further confirmed by 13 C NMR (49.8, 4.7 ppm).

E j em lo 5 347 mg of BAAE were dissolved in 3 mL of THF. The solution was divided into two parts. To one portion was added a catalytic amount of HCl, while to the other a catalytic amount of NaOH was added. Both solutions showed hydrolysis to the bis diol (BAPD), as determined by HPLC and comparison with the authentic material manufactured by the synthesis of the prior art (E g pse 2). Example 6 1.0 g of 5-NIPDA was dissolved in 20 mL of glacial acetic acid. One mL of 30% hydrogen peroxide was added and the reaction mixture was heated to 88 ° C. After three hours, the HPLC showed a 9% conversion with an 80% selectivity to the diol (BAPD). The water in the peroxide led to the hydrolysis of the epoxide and to 8% hydrolysis of the 5-NI PDA to the 5-nitro-isoftalic acid.The epoxidization proceeds through the in situ generation of the acetyl peroxide from the peroxide of hydrogen and acetic acid.

It is noted that, in relation to this date, the best method known by the applicant to carry out the aforementioned invention is the conventional one for the manufacture of the objects or substances to which it refers.

Claims (16)

1. CLAIMS Having described the invention as above, it is drafts < X? D peepie to the ca tmicb in the following reivipdication: A process for the production of a compound of 2, 3 -di p droxipropi lamino, where the process is characterized perqué comprises the reaction steps of: i obtain n composed of N-ac io c K, K-b: sac? Allylamino; (ii) epoxidizing the allylamino compound to give an "N-acyl or N, N-bisacyl epoxypropyl ammonium compound; and (iii) hydrolyzing the epoxypropyl lamino compound to give a compound of 2,3-dihydroxypropyl 1 ami. do not .
2. 2. The process according to claim 1, characterized in that the allylamino compound is of the formula: CH2 = CH-CB2N (H) n (R1) 2_n where n is zero or I and R is an acyl group contains up to 50 carbons.
3. 3. The process, according to claim 2, characterized by R * is acetyl.
4. The process, in accordance with the rei indication 2,: characterized by that p is i and R is a benzoyl group.
5. 5. The process according to claim 4, characterized in that the allylamino compound is the bis-allylamide of 5-nitro-isophthalic acid.
6. 6. The process, according to claim - * - characterized in that the acyl group is an arylcarbonyl group substituted with iodine.
7. 7. The process according to claim 1, characterized in that it also comprises at least one of the following steps: (iv) iodinating a 2,3-dihydroxypropyl-1-amino-carbonyl-phenyl compound; (v) converting a phenol substituent group to a 2,3-dihydroxy-1-aminocarbonyl-1-ene compound or a solubilizing group; and (vi) conjugate two 2,3-dihydroxypropyl-aminoacarbonyl-phenyl compounds to produce a dimeric compound, thereby producing an iodinated contrast agent for radiography.
8. 8. The process according to claim 7, characterized in that the allylamino compound is the bis-allylamide of 5-nitro-isopic acid and that steps (iv) and (v) are carried out to give iohexol.
9. 9. The process, according to claim 1, characterized in that the epoxidation in step (li) is carried out using an oxidant.
10. 10. The process, according to claim 1, characterized in that the epoxidation in step (ii) is carried out using catalytic oxidation.
11. 11. A compound, characterized in that it is N-acyl or N, N-bis acyl-allylated.
12. 12. The compound according to claim 11, characterized in that it is N-acetyl or N, -bi s ace t i 1 -alylamine.
13. 13. The compound according to claim 11, characterized in that it is a 1,3-bis (allylaminocarbonyl) benzene.
14. 14. The compound according to claim 11, characterized in that it is the bis (al-amide) of 5-nitro-isophthalic acid.
15. 15. The compound according to claim 11, characterized in that it is 1, 3-bis (allylaminocarbonyl) -2,4,4-riyodo-5-ni t-benzene.
16. 16. The N-acetyl- or N, N-bi epoxide forms the 1-allylamine, and the epoxides of the compounds according to claims 14 and 15.