CZ276799A3 - Process for preparing 2,3-dihydroxypropylamino derivatives - Google Patents

Abstract

The process for preparing 2,3-dihydroxypropylamine derivatives includes reaction steps: i) recovering the allylamine compound, ii) epoxidizing said allylamine compounds obtaining epoxypropylamine and (iii) hydrolyzing said epoxypropylamine the compound to obtain a 2,3-dihydroxypropylamine compound. This method can be used to make a simple 2,3- dihydroxypropylamine compounds such as APD, or complex compounds such as BAPD (intermediate product iohexol).

Description

Technical field

The invention relates to a process for the manufacture of iodinated X-ray contrast agents, to key intermediates for the manufacture of such contrast agents, and to a process for the manufacture of said intermediates.

BACKGROUND OF THE INVENTION

Iodinated organic compounds, especially triiodophenyl monomeric and dimeric compounds, have long been established and widely used as x-ray contrast agents.

First, the compounds (e.g. iobenzamate, ioglycamate, iothalamate, iocarmate, iopanoate, available metrizoate, iocetamate, iofendylate, ioglicate, ioserate were commercially available, but in the ionic iodipamide, iodamide, iodoxamate, iopronate, ioxoxate, ioxoxate) non-ionic compound commercial iodinated X-ray contrast agents (such as iohexol, iopamidol, iomeprol, iopentol, iopromide, iosimide, iotasul, iotrolan, ioversol, metrizamide and iodixanol) having reduced side effects and can be administered at high concentrations parenterally.

Nonionic compounds draw their necessary water solubility from the presence of nonionic solubilizing groups (such as a hydroxyalkyl group) in their molecular structures. Thus, for example, iohexol, iopentol and iodixanol have monomeric and dimeric triiodophenyl structures incorporating solubilizing hydroxyalkyl groups as shown below:

• ··· ····

Η

AND

Η Η

I I

IODKANOL

The preparation of such compounds involves the introduction of a 2,3-dihydroxypropylamine group on ring-bound carbonyl. As described by Haavaldsen et al., Acta Pharm. Suec. 20, 219-232 (1983), this can be achieved by reacting 3-amino-1,2-propanediol (APD) with a ring-linked carboxyl group. A similar reaction is discussed in US-A-42509113 (Nyegaard and Co.).

Thus, ADP, 3-amino-1,2-propanediol was a critical reagent for the synthesis of commercial 2,3-dihydroxypropylaminocarbonyltriiodophenyl X-ray contrast agents.

·· ···· .. ......

· ··· · ···· · ···. . Ií ........

* ~ and · · · *

However, the main problem was the production of APD with a sufficiently high purity (eg> 99.9%). One synthetic approach to 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 reaction product is a mixture of APD and 2-amino-1,3-propanediol. Purification of the reaction product requires very difficult distillation since the difference between the boiling points of the two aminodiols is very small.

Another possible approach was epoxidation of allyl chloride, hydrolysis to form 1-chloro-2,3-propanediol and replacement of chlorine with ammonia to obtain APD. However, the basic conditions used may lead to the re-formation of the epoxide, where some of the undesired 2-amine products are formed by reaction with ammonia. Therefore, difficult distillation is again necessary to obtain APD of high purity.

Another approach completely avoided the use of epoxides and used the generation of a diol group directly from the allyl group by oxidation with osmium tetroxide (see US-A-5191119; Cook Imaging). However, this approach involves the use of not only osmium tetroxide but also isophthaloyl chloride as an intermediate. Isophthaloyl chloride synthesis is hostile to the environment and the use of highly toxic osmium tetroxide in one of the final manufacturing steps of the product to be injected into patients is unacceptable.

SUMMARY OF THE INVENTION

The present inventors have now found that 2,3-dihydroxypropylamine compounds (such as APD) can be produced without contamination by 2-amine products by epoxidizing allylamine with <RTIgt;

·· · ··

- 4 subsequent hydrolysis. In addition, the epoxidation and hydrolytic reaction can be carried out on an allylaminocarbonylphenyl compound, making the use of APD completely unnecessary in the production of contrast agents such as iohexol.

Thus, in one aspect, the invention provides a process for producing a 2,3-dihydroxypropylamine compound, said process comprising the reaction steps of:

(i) recovering the allylamine compound;

(ii) epoxidizing said allylamine compound to obtain an epoxypropylamine compound; and (iii) hydrolyzing said epoxypropylamine compound to obtain a 2,3-dihydroxypropylamine compound.

Most simply, the process of the invention may exhibit allylamide as the allylamide starting compound for step (i) and APD as the 2,3-dihydroxypropylamine product of step (iii).

To increase the reaction rates or yields during the reaction, it may be desirable to select an N-substituted or N, N-disubstituted compound as the allylamine starting compound, wherein the substituents are chosen to reduce the ability of the nitrogen to act as an electron donor. The allylamine starting compound will preferably have one or two N-acyl substituents. Such substituents may be small (eg, groups containing up to 6 carbon atoms) or large (eg, groups containing up to 50 carbon atoms) and may be removed in the hydrolysis step (iii) or may be left in the 2,3-dihydroxypropylamine product of step (iii).

• ·

• · »ww ^w • · • · ·· • · • · • · ·· ·· ♦ - 5 - ·· «· · · ·; • · · · · · · · · · _# ♦ • ··· ··· · · · · ··· ·· ·· ♦ · Examples of suitable acyl groups groups include alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,

alkarylcarbonyl and arylalkylarylcarbonyl groups in which all alkyl or alkylene structures may be straight or branched chain and in alkyl or alkylene structures all non-acylcarbonyl backbone carbon atoms may be replaced by nitrogen or oxygen atoms or substituted by oxo or hydroxy, other groups in which the aryl groups themselves are optionally substituted, for example, nitro, halo (e.g. iodo), alkylaminocarbonyl, alkenylaminocarbonyl, amino, alkylamino and N-alkyl-acylamino. Aryl groups will preferably be carbocyclic groups of 6 to 10 ring atoms and the alkyl, alkylene, alkenyl and acylamino groups will preferably contain no more than 6 carbon atoms; for example, it will be methyl, ethyl, propyl allyl, vinyl, acetamide and the like.

Thus, such acyl groups will contain structures that are present in X-ray contrast agents such as iohexol or in intermediates of such agents (e.g., iodinated compounds).

Preferred starting materials for step (i) of the process of the invention include N, N-bisacylallylamines (e.g. Ν, Ν-bisacetylallylamine) and 1,3-bis (allyaminocarbonyl) benzenes (e.g. 1,3-bis (allyaminocarbonyl) -5-nitrobenzene, and 1,3-bis (allyaminocarbonyl) -2,4,6-triiodo-5-nitrobenzene). N, N-bisacetylallylamine can be prepared, for example, by treating acetic anhydride on allyamine while 1,3-bis (allyaminocar).

- 6 bonyl) benzenes can be prepared, for example, by reacting an alkylamine with an isophthalic diester, e.g., a methyl ester.

Thus, by way of example, Reaction Schemes 1 and 2 below illustrate the use of the process of the invention to produce simple structures such as APD and more complex structures such as 5-nitro-isophthalic acid bis (amide-1-propane-2,3-diol) (BAPD) , a key intermediate in the production of iohexol. In fact, BAPD is an intermediate product commonly produced by reacting APD with 5-nitro-isophthalic acid or its dimethyl ester.

99

0

Scheme 1

9 0099

0 9 0 99

0 0 0 (APD)

The oxidation of the allyl group can be carried out with a variety of oxidation and / or catalytic systems in the process of the invention. Suitable oxidizing agents include air, oxygen, hydrogen peroxide, perchlorate, and organic peroxides such as metachloroperbenzoic acid. Oxidants such as air, oxygen and hydrogen peroxide can be used to localize the generation of more efficient types of oxidizing agents, for example, a mixture of hydrogen peroxide and acetic acid will form the oxidizing agent peracetic acid. A wide variety of metals and their compounds (e.g., oxides, complexes and the like) can be used as a catalyst where used. Examples of suitable catalyst metals include Ti, V, Mn, Fe, Co, Mo, Ru, Rh, W, Re and Os (although 0s0 ₄ and RuO ₄ should not be used). For examples of catalytic systems, reference may 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 choice of catalyst will depend to a large extent on whether the diolamine product itself is to be used as the contrast agent or whether it is only a later intermediate to form the contrast agent. In such cases, the use of highly toxic catalysts should be avoided.

The epoxypropylaminocarbonylphenyl compounds to be produced using the process of the invention, such as the BAAE compound, are novel in themselves and constitute a further aspect of the invention. Similarly, the 5-NIPDA product is novel and constitutes another aspect of the invention.

Where the intended product of the process of the invention is APD, direct 2,3-dihydroxylation of the allylamine starting compound (e.g., allylamine, N-acetylallylamine or Ν, bis-bis-acetylallylamine) can be performed using, for example, catalysts such as OsO ₄ and RuO ₄ . even though it is a small molecule that can be easily obtained from the starting material and •

- 9 polluting catalyst by distillation. In a further aspect, the invention provides a process for the manufacture of APD, said process comprising 2,3-dihydroxylation of optionally N-acetylated or Ν, Ν-bisacetylated allylamine and, if desired, hydrolysis of N-acyl- or N, N-bisacyl-2; 3-dihydroxypropylamine reaction product.

In the process of the invention, the hydrolysis step, step (iii), can be carried out using conventional hydrolysis techniques, for example acid catalysis. The hydrolysis conditions may be selected to remove or omit any acyl substituent on the nitrogen of epoxypropylamine.

For the preparation of 2,3-hydroxypropylamine X-ray contrast agents, in particular non-ionic contrast agents containing a 1- (2,3-dihydroxypropylaminocarbonyl) -2,4,6-triiodophenyl structural component such as iohexol, iopentol and iodixanol, the process of the invention may comprise one or more of the following manufacturing steps:

(iv) iodinating the 2,3-dihydroxypropylaminocarbonylphenyl compound;

(v) converting a phenyl substituent of the 2,3-dihydroxypropylaminocarbonylphenyl compound into a solubilizing group such as a hydroxylated and / or alkoxylated group such as an alkylaminocarbonyl or alkylcarbonylamino group (optionally carrying an N-acyl substituent such as CH ₃ CO); and (vi) combining two 2,3-dihydroxypropylaminocarbonylphenyl compounds to form a dimeric compound.

• 9,999 • 9,999 • 9 ·

• 9 ·· ···

• 9 9 9

9 9 ·

999 999 *

99

Thus, as described by Haavaldsen (supra), contrast agents can be conveniently produced according to a procedure such as the following:

nonionic manufacturing

(3)

wherein the iodination step (D) is omitted if the iodination was performed before, for example, before formation of the 5-nitroisophthalic acid diester starting compound (1), or iodination was performed before steps (A), (B) or (C). [Haavaldsen (above) suggested iodination before step (C).] The R groups in the above scheme are not differentiated. The specific groups chosen would undoubtedly depend on the desired end product. When using the method according to the invention to produce:

4

9999

9 9

999

Thus, iohexol will suitably include step (A) comprising reacting 5-NIPDE with allylamine to form 5-NIPDA, epoxidizing to BAAE, and hydrolyzing to form BAPD. This compound is then reduced, acetylated, N-hydroxyalkylated and iodinated.

The patents and other references cited herein are incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described with reference to the following non-limiting examples. The starting compounds, the intermediates and end products were analyzed by HPLC (high performance liquid chromatography) and ¹³ C-NMR (nuclear magnetic resonance analysis using ¹³ C). The HPLC system used was based on absorption at 240 nm (absorbing the benzene core in this region). The HPLC system was all-glass Dionex; the column used was Supercosil LC-18 DB; the eluent was 72% methanol, 6.0 mmol.l ^-1 tetrabutylammonium disulfate and 4.0 mmol.l ^-1 sodium hydroxide. The flow rate was 1.0 ml / min and the sample volume was 25 μΐ; The UV detector was used at 240 nm. The HPLC retention times, in minutes, are given in Table 1 below.

Table 1 5-Nitroisophthalic acid bis (amide-1-propane-2,3-diol) I 2.87

N- (propane-2,3-diol) -benzamide 2.87 bis (1-propane-2,3-diol) 5-nitroisophthalic acid (BAPD) II

2, 98 • 4

- 12 44 4444 • 4 • 444 «4 44 · · 4

4 ··· 444

444 ··

4 4

4 4

4

4 44 5-nitroisophthalic acid bis (allylamide-epoxide) 5-nitroisophthalic acid (BAAE) 5-nitroisophthalic acid N-allylbenzamide epoxide 1-allylamide-3-allylamide 5-nitroisophthalic acid epoxide

N-allylbenzamide bis (allylamide) 5-nitroisophthalic acid (5-NIPDA) m-chloroperbenzoic acid m-chlorobenzoic acid

3.12

3.30

3.40

3.48

3.58

4, 05

4.50 5-nitroisophthalic acid dimethyl ester (5-NIPDE) 6.25

It should be noted that (a) retention times are prolonged when freshly prepared eluent is not used and (b) that BAPD gives two peaks (peaks).

Table 2 below gives the determination of the maximum (peak) of ^1j C for 5-nitroisophthalic acid derivatives, namely 5-NIPDA, BAAE and BAPD:

O

O

00 ·· • · 0

000 0 0 · 0000 000

00 0 0 0 ·

5-NIPDA BAAE BAPD E 163, 6 164, 0 166, 5 D 147, 9 148 148 AND 134.8 135, 1 135, 6 (B) 132.3 130, 7 132, 1 C 124, 2 124 125 F 41, 8 41.0 43.1 G 136, 0 44.7 63, 9 H 115, 7 49, 8 70, 8

Example 1

N-allylbenzamide (NAB) Monomer-Polymer Laboratories as 99.5%. Its purity was determined to be 99.9% using chloroform and NAB. NAB-purified 1.05 g of silica gel was treated with a solution of 2.14 g of m-chloroperbenzoic acid (MCPBA) in 15 ml of tetrahydrofuran (THF). After 64 hours at room temperature, HPLC determination showed no MCPBA left. The conversion was 89.7% with 15.8% selectivity to BAPD and 78.7% selectivity to N-allylbenzamide epoxide.

Example 2 (comparative)

To 60 ml of boiling methanol was added 23.9 g of 5-nitroisophthalic acid dimethyl ester followed by 21.84 g of 1-aminopropane-2,3-diol (APD). A white solid formed. After addition of an additional 100 mL of methanol, the mixture was heated all weekend. The white product was then filtered from the hot solution, washed with a small amount of methanol, and dried in a vacuum oven. Yield of isolated

5-Nitroisophthalic acid (BAPD) bis (amide-1-propane-2,3-diol) was 19.5 g. It was identified by the technique. ¹ H and ¹³ C NMR.

Example 3 grams of 5-nitroisophthalic acid dimethyl ester (5-NIPDE) was dissolved in 75 ml of methanol and 100 ml of allylamine. The solution was heated under nitrogen at reflux for approximately 10 hours. Thin Layer Chromatography (TLC) showed that the conversion was complete. About 1 L of ethanol / water (mixed 1: 1) was then added. The solution was heated and brightened at 59 ° C. Then a smaller amount of water was added and the temperature was raised to 75 ° C. The solution was then allowed to slowly cool to room temperature while stirring. The product was filtered and dried in a vacuum oven at 50 ° C. The product was then dissolved in hot ethanol and slowly cooled to 4 ° C. Filtration and repeated drying afforded 47.82 g of the product (79% yield). From the remaining filtrates, an additional amount of product can be easily obtained (second yield; total yield then 94%). The obtained material was identified as 5-nitroisophthalic acid bis (allylamide) (5-NIPDA) by HPLC, NMR and MS (mass spectrometry).

Example 4

1.27 g of 5-NIPDA was dissolved in 15 ml of THF. For chloroperbenzoic acid (MCPBA), a balance of 57% of its peroxide activity was determined. 3.09 g of this material was added, representing a 1.16-fold excess of peroxide relative to the allyl substituents. The reaction mixture was stirred at room temperature and HPLC showed 80% conversion in about 6 hours. The reaction was allowed to proceed overnight. Thereafter, it was 0900 909 909 9 9 999 9 9

- 15 conversion to diepoxide (BAAE) complete. The process also included the addition of methylene chloride and water containing sodium carbonate or bicarbonate. The organic fractions were combined. Removal of the solvent yielded 0.80 g of a glassy mass. HPLC showed a sample purity of 73%. Mass spectrography showed a peak (peak) corresponding to the addition of two oxides corresponding to bisallylepoxide (BAAE), further confirmed by ¹³ C NMR (49.8; 44.7 ppm).

Example 5

347 mg of BAAE was dissolved in 3 ml of THF. The solution was then divided into two portions. A catalytic amount of HCl was added to one portion, while a catalytic amount of NaOH was added to the other portion. Both solutions showed hydrolysis to bis-diol (BAPD) as determined by HPLC and comparison with the authentic compound prepared by the synthesis of the former method (Example 2).

Example 6

1.0 g of NIPDA was dissolved in 20 ml of glacial acetic acid. Then 1 ml of 30% hydrogen peroxide was added and the reaction mixture was heated to 88 ° C. After three hours, HPLC analysis showed a 9% conversion with 80% diol selectivity (BAPD). Water in peroxide led to epoxy hydrolysis and 8% hydrolysis of 5-NIPDA to 5-nitroisophthalic acid. Epoxidation continued via local (sine) generation of acetyl peroxide from hydrogen peroxide and acetic acid.

Represented by:

Claims (16)

- 16 PATENT CLAIMS 1. A process for the preparation of 2,3-dihydroxypropylamino derivatives wherein said process comprises the reaction steps of: (i) obtaining an N-acyl- or N, N-bisacyl-allylamine compound; (ii) epoxidizing said allylamine compound to obtain an N-acyl- or N, N-bisacyl-epoxypropylamine compound; and (iii) hydrolyzing said epoxypropylamine compound to obtain a 2,3-dihydroxypropylamine compound. A process for the preparation of 2,3-dihydroxypropylamino derivatives according to claim 1, characterized in that said allyamine compound has the formula CH ₂ = CH-CH ₂ N (H) _n (R ¹ ) _{2 - n} , wherein n is zero or 1 and R ¹ is an acyl group containing at most 50 carbon atoms. 3. A process for the preparation of 2,3-dihydroxypropylamino derivatives according to claim 2, wherein R is acetyl. A process for the preparation of 2,3-dihydroxypropylamino derivatives according to claim 2, characterized in that n is ^{1 and} R ¹ is a benzoyl group. A process for the preparation of 2,3-dihydroxypropylamine derivatives according to claim 4, wherein said allylamine compound is 5-nitroisophthalic acid (bis) allylamide. 6. A process for the preparation of 2,3-dihydroxypropylamino derivatives according to claim 1, wherein the acyl group is an iodo substituted arylcarbonyl group. 7. A process for the preparation of 2,3-dihydroxypropylamino derivatives according to claim 1, further comprising at least one of the following steps: (iv) iodinating the 2,3-dihydroxypropylaminocarbonylphenyl compound; (v) converting the phenyl substituent of the 2,3-dihydroxypropylaminocarbonylphenyl compound to a solubilizing group; and (vi) combining two 2,3-dihydroxypropylaminocarbonylphenyl compounds to form a dimeric compound. A process for the preparation of 2,3-dihydroxypropylamine derivatives according to claim 7, characterized in that said allylamine compound is 5-nitroisophthalic acid (bis) allylamide and steps (iv) and (v) are carried out to obtain iohexol. A process for the preparation of 2,3-dihydroxypropylamino derivatives according to claim 1, characterized in that the epoxidation in step (ii) is carried out using an oxidizing agent. 10. A process for the preparation of 2,3-dihydroxypropylamino derivatives according to 4 «• · 9 9 • «·· · 9 9 t t 9 9 9 Claim 9, characterized in that the epoxidation in step (ii) is carried out using catalytic oxidation. 11. N-acyl- or N, N-bisacyl-allylamine. 12. A compound according to claim 11 which is N-acetyl- or N, N-bisacetyl-allylamine. Compound according to claim 11, characterized in that it is 1,3-bis (allylaminocarbonyl) benzene. 14. A compound according to claim 11, wherein the compound is 5-nitroisophthalic acid bis (allylamide). A compound according to claim 11, characterized in that it is 1,3-bis (allylaminocarbonyl) -2,4,6-triiodo-5-nitrobenzene. N-acetyl- or N, N-bisacetyl-allylamine epoxide and epoxides of the compounds according to claims 14 and 15.