GB2331098A - An N-Alkylation process - Google Patents

Abstract

A process for N-alkylation of a substrate to yield an N-alkyl group containing product comprises reacting said substrate with an alkylating agent containing an alkylatable group or a precursor therefor, characterised in that said substrate and/or said alkylating agent is reacted previously or simultaneously with a boron oxyacid, and in that said process further comprises deprotecting boron protected groups and optionally recovering said product.

Description

Process This invention relates to a process for Nalkylation to introduce a group which is itself alkylatable, eg a hydroxyl-alkyl group, more particularly a process for such N-alkylation of compounds containing 1,2 and/or 1,3 diol structures.

Where N-alkylation is effected on a hydroxyl group containing substrate, even though N-alkylation occurs preferentially, competing O-alkylation reactions can occur resulting in reduced yield and undesired byproduct formation. Such N-alkylation is even more problematic where the alkyl group being introduced itself is hydroxylated as the N-alkylated product is susceptible to O-alkylation of the N-alkyl group that has been introduced.

Thus for example, in the case of pharmaceutical compounds prepared via multistep synthetic procedures, where N-hydroxy-alkylation is effected at a late stage in the synthetic procedure, the O-alkyl by-product formation significantly reduces production efficiency since the production of the N-alkylation substrate may have involved the use of expensive reagents and complex and time-consuming synthetic steps. Moreover since the O-alkyl by-products frequently have very similar characteristics in terms of solubilities, etc. the work up of the N-alkylated product to remove these O-alkyl by-products involves significant use of equipment and time and may contribute to a further drop in overall yield.

This is particularly important in the case of the iodinated organic compounds, generally triiodophenyl compounds, which are used widely as contrast agents for X-ray imaging. For these compounds, the expensive iodination step is usually effected at a late stage of the multistep synthesis but is generally followed directly or indirectly by N-alkylation of the nitrogens of one or more amide functions on the phenyl ring, commonly the nitrogen of an acylamino substituent.

The N-alkylated amide groups are important components of the overall contrast agent molecule in that they may impart water solubility to an otherwise highly lipophilic triiodophenyl structure.

Thus, by way of example, in the preparation of the X-ray contrast agent iohexol described in GB-A-1548594, the triiodophenyl intermediate

(hereinafter "compound A"), is reacted in propylene glycol with the alkylating agent 1-chloro-2,3- propanediol to produce iohexol

IOHEXOL In the preparation of iopentol, described in EP-A105752, compound A is reacted with the alkylating agent l-chloro-2-hydroxy-3-methoxy-propane, and in the preparation of iodixanol described in EP-A-108638 compound A is reacted with the alkylating (coupling) reagent epichlorohydrin.

In each case N-alkylation occurs at the acetyl amino nitrogen of compound A.

The N-hydroxy-alkylation of a hydroxyl group containing substrate such as compound A is accompanied by O-alkylation side reactions, generally as shown below in Scheme A (using for illustrative purposes the reaction to produce iohexol but, as in the subsequent Schemes B to D, using a simplified formula to represent the parts of the molecule not involved in N- or O- alkylation).

SCHEME A

NH'COH LvROH LVROH Staning Material, NH OR eg Compound A \ LvROH OH H EWO LVROH < LvROH ROH (jH DESIRED PRODUCT \ I I EWG, %%011H LVROH 'YoR Nh \ \ ROH OH bH Lv LvROH EWG Y EWG ~Y OH '6"" OR ROH R-OH ROROH OH OH (where EWG is an electron withdrawig group, ROH is the hydroxyalkyl group being introduced, Lv is a leaving group, LvR-OH is the alkylating agent and Y is the rest of the molecule of the N-alkylation substrate).

Thus there is a need for an N-hydroxy-alkylation procedure which can be used with the polyhydroxylated intermediates in X-ray contrast agent synthesis, and in particular for a procedure which can be used with an aqueous rather than organic solvent system so as to reduce environmental problems.

We have now found that by using boron oxyacid (e.g. boric acid, borates, boronic acid, etc) as diol protecting agents, the N-hydroxy alkylation of such polyhydroxylated X-ray intermediates may be effected efficiently to produce products with a significant reduction in the production of O-alkyl by-products, and that moreover the N-hydroxy-alkylation reaction may be effected in water.

The difference in by-product formation is conveniently illustrated by the following scheme B, covering for example the conversion of compound A to iohexol using boron oxyacid diol protection.

SCHEME B

EwGNHYNŎH EWG, oOH OH Starting Material, ROH OH eg Compound A DESIRED PRODUCT B(OH)3 Deprotection yO \ OH, LVROH EWG, Y O-F(-OH ROll OH dH LVROH LVROH EWG \O LvROH EWG ys LvRHH I ROll OR OH OH OH OH OH Deprotection Deprotection NH'XOH EWG, OH OH ROH OH Starting Material DESIRED PRODUCT As can be seen by comparison of schemes A and B, using scheme B, after deprotection, the end products are essentially only the desired end product and the starting material (which can be recovered and reused).

The diol protecting boron oxyacid may furthermore be used to good effect when a substrate without diol groups is to be N-alkylated with a bis-hydroxy-alkyl group, as described below. In this context, the presence of a boron oxyacid diol protecting group in the N-hydroxy alkylation reaction medium serves to inhibit formation of by-products in which the N-hydroxy-alkyl groups introduced in the reaction are subsequently 0alkylated. This may be seen from scheme C below: SCHEME C

OH OH NH 2,3.HPA y'N,EWG ' $;3.HPA Y 'EW6 Y EWG N DESIRED PRODUCE X y EWG 1OH DESIRED OOH B(OH)3 0 Deprotection HO (4OH XOH y, NsEWG N EWG (where 2,3-HPA is a 2,3-bishydroxypropylating agent) Thus viewed from one aspect the invention provides a process for N-alkylation of a substrate to yield an Nalkyl group containing product which comprises an alkylatable moiety in said N-alkyl group, said process comprising reacting said substrate with an alkylating agent containing an alkyl at able group or a precursor therefor, characterised in that said substrate and/or said alkylating agent is reacted previously or simultaneously with a boron oxyacid, and in that said process further comprises deprotecting boron-protected alkylatable groups, eg hydroxyl groups, and optionally recovering said product.

The substrate for the process of the invention need not but preferably does contain an N-hydroxy alkyl group, in particular a 1,2 or 1,3 diol group (ie. with hydroxyls attached to adjacent carbons in the substrate structure or to carbons separated by a further carbon in the substrate structure), more particularly a linear or branched thio or hydroxy C110, or more preferably C3 8,alkyl group, and most preferably a hydroxy C36 alkyl group. The alkyl group introduced by the alkylating agent in the process of the invention preferably contains a hydroxy group, in particular a 1,2 or 1,3 diol group, more particularly a linear or branched hydroxy Cll0, more preferably C3,alkyl group, or a precursor therefor, e.g. an oxirane group. The hydroxyalkyl groups introduced by the alkylating agent preferably contain two hydroxyl groups; nevertheless they may contain 1 or 3 or more hydroxyl groups.

In one preferred embodiment of the process of the invention, the substrate is an anilide with the ring attached nitrogen substituted by an electron withdrawing group, e.g. an acyl-anilide or sulphonyl-anilide. In an especially preferred embodiment, the substrate is an n, n+1 or n, n+2 bishydroxyalkylaminocarbonyl-acylanilide.

In this embodiment the process may comprise: reacting the n,n+l or n,n+2 bishydroxyalkylaminocarbonylacylanilide with a boron oxyacid and simultaneously or subsequently with the alkylating agent; subsequently deprotecting boron protected diol groups; and optionally recovering the N-alkylated bishydroxyalkylaminocarbonylacylanilide.

By n,n+1 and n,n+2 it is meant that the hydroxyalkyl groups referred to have hydroxy groups on neighbouring carbons or on carbons separated by one carbon atom. Such diol groups react with boron oxyacids to produce cyclic boron protected diol groups, e.g. groups of formula

(For simplicity, the negative charge on the boron and the countercation (ie. M+) are omitted in the formulae elsewhere in this text).

The n,n+l and n,n+2 bishydroxyalkyl groups may if desired contain more than two hydroxy groups - however where other hydroxy groups are present the boron diol protection will serve to reduce but may not entirely eliminate 0-alkyl by-product formation.

A further preferred embodiment of the process of the invention involves reacting an organic compound with a primary or secondary amino (or more preferably amido) compound with an alkylating agent which introduces a bis-hydroxyalkyl group. In this embodiment the process may conveniently involve: reacting the organic compound with a n,n+l or n,n+2 bishydroxyalkylating agent (e.g. a haloalkanol, or a haloalkyloxirane, for example epichlorohydrin, or analogs or derivatives thereof) in the presence of a boron oxyacid; subsequently deprotecting boron protected diol groups; and optionally recovering the N-bishydroxyalkylated organic compound.

The n,n+l and n,n+2 hydroxyalkyl groups in the substrates and end products of the processes of the invention preferably do not have hydroxyls on the a carbon, i.e. the nitrogen attached carbon.

The n,n+l and n,n+2 hydroxyalkyl groups in the substrates and end products of the processes of the invention conveniently contain 3 to 10 carbons, especially 3 to 6 carbons, and preferably 2, 3 or 4 hydroxyls, especially preferably 2 hydroxyls.

In the processes of the invention, the N-alkylation substrates are preferably compounds of formula I

where each A is independently hydrogen or halogen, more preferably, iodine; each R7 is independently a C16 hydroxyalkyl group, a group CONHR2 or a group NHR: optionally attached to the phenyl ring by an oxygen or sulphur atom or by a sulphoxide or sulphone group; each R1 is independently a hydrogen atom, a cyano group, an optionally hydroxy, alkoxy, halo, or aryl substituted alkyl group, an optionally hydroxy, halo, alkoxy or alkyl substituted aryl group or an acyl group, Rl preferably being a group R3CO, R3SO or R3SO2 (where R3 is an optionally hydroxy, halo, alkoxy or alkyl substituted aryl group or an optionally hydroxy, alkoxy, halo or aryl substituted alkyl group); and each R2 is independently a hydrogen atom or an optionally hydroxy, alkoxy, halo or aryl substituted alkyl group, at least one R2 preferably being a n,n+l or n,n+2 bishydroxyalkyl group.

In the compounds of formula I, each alkyl or alkylene moiety preferably contains 1 to 6 carbons; each halo substituent is preferably an iodine atom; each aryl group is preferably a 5 to 10 ring atom group optionally containing one, two or three ring heteroatoms selected from 0, N and S, especially preferably a phenyl group; and optional substitution includes substitution by more than one of the listed substituents.

Particularly preferred as N-alkylation substrates are compounds of formula Ia, Ib, Ic, Id, Ie and If

(where each R4 independently is a C3-5 hydroxyalkyl group having at least two hydroxyl groups on neighbouring carbons or on carbons separated by one other carbon; and each R5 is independently hydrogen or a C13 alkyl group).

Especially preferred as N-alkylation substrates are compounds of formula Ig

(where R, is hydroxymethyl, hydroxyethyl, 2,3-dihydroxy 1-propyl, l,3-dihydroxy-2-propyl or CONHR4; and each R4 is a 2, 3-dihydroxy-l-propyl, 1, 3-dihydroxy-2-propyl or 1,3,4-trihydroxy-2-butyl group), in particular compound A.

In the processes of the invention, the alkylating agent used may be any compound capable of reacting with the nitrogen containing substrate to introduce an appropriately substituted alkyl group at a nitrogen atom. Preferably it contains the desired substituted alkyl group (or a precursor therefor) and a leaving group, e.g. a chlorine or an epoxy oxygen. Nitrogendisplaceable leaving groups are well known in synthetic organic chemistry. If desired, the alkylating agent may be a bifunctional agent, containing for example two leaving groups which may be the same or different, so that the N-alkylation reaction serves to couple together two molecules of the nitrogen containing substrate as in the synthesis of iodixanol. Particularly preferably, the alkylating agent contains a hydroxy group or a precursor therefor (e.g. an epoxide group, a protected hydroxyl group or an oxo group) and especially preferably it contains two or more, e.g. 2, 3 or 4, hydroxyl groups or precursors therefor. The "alkyl" moiety that the agent serves to introduce preferably contains 1 to 10 carbons, especially 1 to 8 carbons, particularly 2 to 6 carbons, unless alkylation involves coupling two aromatic molecules in which case the "alkyl" groups will conveniently contain up to 50 atoms, preferably up to 60 atoms. The alkylating agent may thus be represented by formula III LV-(CH (H) ,~,~, (Z),(LV),).H (III) where each Lv is a leaving group, optionally an oxygen atom which is also bonded to an adjacent carbon to produce an oxirane ring; m is 0 or 1; p is 0 or 1; Z is a hydrogen atom, a hydroxyl group or an organic moiety conveniently containing up to about 80 atoms, at least one Z being a hydroxy group; and n is 1 to 10; at least one p is 1 and the sum of all p's preferably being 1, 2 or 3. Where Z represents an organic moiety, this is preferably an alkyl or aryl group optionally attached via an oxygen or sulphur atom or an SO or SO2 group and optionally substituted by one or more groups selected from hydroxy, alkoxy, halo, oxo, cyano, alkyl, aryl, and oxyacid.

Particularly preferred alkylating agents are 1halo-2, 3-propanediols, e.g l-chloro-2, 3-propanediol, halohydrins, e.g epichlorohydrin, 2-halo-1, 3- propanediols, e.g 2-chloro-1, 3-propanediol, and 1-halo3-alkoxy-propan-2-ols, e.g l-chloro-3-methoxy-propan-2ol. Other appropriate alkylating agents are described by Bjrsvik et al. in Acta Chem Scand. 48 : 446-456 (1995).

The boron oxyacid used in the processes of the invention may be used in the free acid forms (e.g as boric acid, metaboric acid or a boronic acid) or as salts or esters. Examples of borates which may be used include borax, metaborate and ortho-borate. Mixtures of two or more such boron oxyacids may also be used. Where a boronic acid is used, the non-hydroxy substituent on the boron may be any convenient organic moiety, generally selected for its compatibility with the solvent system being used and for its relative nonreactivity with the alkylating agent being used, e.g. an optionally substituted phenyl or lower alkyl group. In general however the preferred diol protecting agent will be boric acid as it is inexpensive and readily obtainable.

The N-alkylation reaction of the processes of the invention can if desired be effected in a "one-pot" reaction with N-alkylation substrate, boron diol protecting agent and N-alkylating agent being reacted together simultaneously. Alternatively the diol protection reaction may be effected before the protected substrate, which may or may not be isolated first, is exposed to the N-alkylating agent. Diol deprotection may conveniently be effected by reducing the pH, e.g to below 5.

The diol deprotection reaction allows both the Nalkylated end product and the N-alkylation substrate to be recovered, in the latter case for optional recycling through diol protection, N-alkylation and diol deprotection.

The overall effect is thus to enable a higher ratio of N-alkylated end product to O-alkyl by-product to be achieved. Following diol deprotection, the boronated residues may readily be removed from the reaction mixture by filtration and reverse osmosis work-up.

Boric acid is a weak monovalent acid which readily esterfies to complex alkoxy borates. Generally such esters are stable in aqueous reaction media at pH's above about 7. In general the highest stability of boron protected diols in aqueous media occurs at the pH where the sum of the charges of the free esterifying species is equal to the charge of the ester. The rate of diol protection and deprotection is rapid.

The protected diols may comprise two diol species protected by the same boron.

In general in boron diol protection, the aqueous dilution of the reagents should be kept as low as possible to maximize the protection of the diol ester formation. However, the reaction medium must have an acceptable viscosity. Thus, by way of example for compound A as the N-alkylation substrate, water contents may be as low as 0.8, e.g. 0.9 to 1.0, mL/g substrate.

The quantity of boron diol protecting agent used will conveniently be at least 0.4 mol B/mol diol group in the substrate (i.e. at least 0.8 mol B/mol substrate where the substrate contains two n,n+1 or n,n+2 diol groups), preferably at least 0.5 molB/mol diol group, especially preferably at least 1.0 molB/mol diol group, e.g. 1.1 to 2.0 molB/mol diol group.

The diol protection is preferably effected in a neutral to alkaline medium, e.g pH 7 to 15, preferably pH 10 to 14. This may be achieved by inclusion of a tolerable base, e.g an alkali metal or alkaline earth metal hydroxide, but preferably a base which is not a primary or secondary amine. The base concentration is preferably at least equivalent to the boron diol protecting group concentration, e.g expressed as OH and H+ equivalents.

During the diol protection and N-alkylating reactions, the pH is preferably monitored and if necessary adjusted to maintain an alkaline level, e.g by addition of small quantities of base or boron diol protecting agent.

Optimal pH and base may be determined for particular N-alkylation substrate/N-alkylating agent combinations.

The quantity of N-alkylating agent used should generally be at least equivalent to the concentration of nitrogens to be N-alkylated, e.g an equivalent ratio of 1:1 to 1.5:1. The optimal ratio may be determined for particular N-alkylation substrate/N-alkylating agent combinations. The N-alkylating agent may be added in a single step, over a series of steps, or continuously.

In general, the processes of the invention are effected at temperatures in the range -20 to +1400C, preferably 0 to 600C. Thus, in a preferred embodiment, N-alkylation substrate (1 equivalent N-H), base, boric acid and water are mixed. The order of mixing is not important but for acid N-H substrates the order water, base, substrate, boric acid is preferred. The quantity of boric acid, B, in equivalents is preferably the product of the number of protectable diol groups in the substrate and a number with a value in the range 0.5 to 2, preferably 1.0. The quantity, OH, of base (in OH equivalents) is preferably given by the equation OH 5 (B + C)D + E where: C is the number of acidic nitrogen attached hydrogens in the starting material; D has the value 0 to 2, preferably 1.0; and E has the value 0-2, preferably 0 for epoxide or alkyl halide alkylating agents and 1 for halohydrin or dialkyl sulphate alkylating agents. For other boron sources than boric acid an appropriately modified version of this equation may be used, taking into account that, for borax or metaborate, hydrolysis yields base and boric acid.

The quantity of water used is preferably the minimum necessary to achieve a reaction mixture with an acceptable viscosity, e.g 0.3 to 5, preferably about 1, L/kg substrate.

The mixing temperature is conveniently 0 to 1000C, preferably 20-50"C; the mixing time is dependent on the mixing temperature and is typically 1 to 24 hours, with mixing conveniently being effected until a clear homogeneous solution is obtained. However, in certain circumstances, the mixture may remain as a suspension.

The pH is measured and if necessary adjusted by addition of base or boric acid.

The mixture is then preferably brought to a reaction temperature in the range 0 to 600C, e.g 10 to 20"C.

The alkylating agent is then preferably added to a total amount, H, in equivalents given by H = 1/F + G where F 2 1, preferably 1 for monoalkylating agents and 2 for bis-alkylating agents, and G is 0 to 1, preferably 0.01 to 0.2 (for the compensation of partial hydrolysis). As indicated above, addition may be stepwise or continuous.

During reaction, pH should desirably be monitored and adjusted if required.

The reaction time will depend on reaction temperature and is typically 2 to 72 hours, e.g 3 to 24 hours.

The reaction may be performed using a pH gradient and/or a temperature gradient, preferably a pH and temperature gradient.

Following the alkylating reaction, the reaction mixture may be worked up by dropping the pH to 5 or below, e.g by addition of hydrochloric acid. Boric acid precipitates and the dispersion is preferably cooled to OOC and maintained at that temperature for 1 to 24 hours, e.g 1 to 3 hours. The reaction mixture may then be filtered cold. Salts in the filtrate may be removed by reverse osmosis and/or ion exchange whereafter the solution may conveniently be evaporated to dryness to give a crude product. Pure N-alkylated end product may be recovered by conventional methods.

The process of the invention is also applicable to N-alkylation of 1-amino-2,3-propane-diols and 2-amino1,3-propane-diols (APDs) in general, e.g compounds in which the nitrogen to be alkylated is or is attached indirectly to the amine nitrogen of the APD (for example as in compound A above), and to N-alkylation of the acylated nitrogen of n,n+l/n,n+2 diol substituted Nacyl-anilides in general. Such processes form further aspects of the invention.

The invention will now be described further with reference to the following non-limiting Examples: Example 1 Iohexol Compound A (1 eqv., 100 g) was dissolved in an aqueous solution of KOH (4.5 eqv., 33.8 g) in water (1.0 volume/weight compound A, 100 ml). Boric acid (2.5 eqv., 20.69 g) was added and the solution was stirred for 124h (preferably 18h) at 100C. The starting pH was > 14.

3-Chloro-1, 2-propanediol (1.10 eqv., 16.28 g) was added to the stirred solution at 100C. The reaction mixture was stirred at 100C and the pH dropped below 13. The pH was then stabilized in the range 12.6 - 13 by adding small amounts of boric acid (in total 0.14 eqv., 1.17 g). After 24h and 48h, samples of 50p1 were taken, diluted in a solution of conc. HC1 (5081) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 78.28 % iohexol, 19.22 % compound A, 2.50 % others.

Results (area-%) after 48h: 86.83 % iohexol, 10.53 t compound A, 2.64 % others.

Example 2 I ohexol Compound A (1 eqv., 100 g) was dissolved in an aqueous solution of KOH (3.5 eqv., 26.29 g) in water (1.0 volume/weight compound A, 100 ml). Boric acid (2.5 eqv., 20.69 g) was added and the solution was stirred for 124h (preferably 18h) at 100C. The starting pH was about 12.4. Glycidol (1.03 eqv., 10.21 g) was added to the stirred solution at 100C. The reaction mixture was stirred at 100C and the pH drifted towards 13. The pH was then stabilized in the range 12.6 - 13 by adding small amounts of boric acid (in total 0.34 eqv., 2.86 g). After 24h and 48h, samples of 5041 were taken, diluted in a solution of conc. HC1 (5041) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 72.75 % iohexol, 23.77 % compound A, 3.48 % others.

Results (area-%) after 48h: 78.63 % iohexol, 16.92 % compound A, 4.45 % others.

Example 3 (Comparative) I ohexol Compound A (1 eqv., 10 g) was dissolved in an aqueous solution of KOH (2 eqv., 1.50 g) in water (1.0 volume/weight compound A, 10 ml). 3-Chloro-1,2- propanediol (1.10 eqv., 1.63 g) was added to the stirred solution at 100C. The reaction mixture was stirred at 100C. After 24h and 48h, samples of 50p1 were taken, diluted in a solution of conc. HC1 (50y1) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 65.5 % iohexol, 23.1 e compound A, 9.5 % others.

Results (area-%) after 48h: 67.1 e iohexol, 17.6 % compound A, 14.1 % others.

Example 4 (Comparative) lohexol Compound A (1 eqv., 10 g) was dissolved in an aqueous solution of KOH (1 eqv., 0.75 g) in water (1.0 volume/weight compound A, 10 ml). Glycidol (1.03 eqv., 1.02 g) was added to the stirred solution at 100C. The reaction mixture was stirred at 100C. After 24h and 48h, samples of 50y1 were taken, diluted in a solution of conc. HC1 (50 l) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 55.3 % iohexol, 25.3 % compound A, 18.5 % others. Results (area-%) after 48h: 54.2 % iohexol, 28.2 % compound A, 16.4 t others.

Example 5 lopentol Compound A (1 eqv., 100 g) was dissolved in an aqueous solution of KOH (3.25 eqv., 24.41 g) in water (1.0 volume/weight compound A, 100 ml). Boric acid (2.75 eqv., 22.76 g) was added and the solution was stirred for 1-24h (preferably 18h) at 200C. The starting pH was about 11.7. Glycidyl methyl ether (1.03 eqv., 12.15 g) was added to the stirred solution at 200C. The reaction mixture was stirred at 200C. The pH increased but not above 13. After 24h and 48h, samples of 50y1 were taken, diluted in a solution of conc. HCl (50&num;1) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 83.12 % iopentol, 11.07 % compound A, 5.81 % others. Results (area-%) after 48h: 85.83 % iopentol, 7.89 % compound A, 6.28 % others.

Example 6 lopentol Compound A (1 eqv., 100 g) was dissolved in an aqueous solution of KOH (4.0 eqv., 30.04 g) in water (1.0 volume/weight compound A, 100 ml). Boric acid (3. 0 eqv., 24.83 g) was added and the solution was stirred for 124h (preferably 18h) at 200C. The starting pH was about 12.4. 3-Chloro-l-methoxy-2-propanol (1.03 eqv., 17.17 g) was added to the stirred solution at 200C. The reaction mixture was stirred at 200C. The pH decreased but not below 10. After 24h and 48h, samples of 50y1 were taken, diluted in a solution of conc. HC1 (50p1) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after solution of KOH (0.5 eqv., 0.38 g) in water (1.0 volume/weight compound A, 10 ml). Glycidyl methyl ether (1.03 eqv., 1.21 g) was added to the stirred solution at 200C. The reaction mixture was stirred at 200C. After 24h and 48h, samples of 50y1 were taken, diluted in a solution of conc. HCl (50y1) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 67.0 iopentol, 22.7 % compound A, 9.4 % others. Results (area-%) after 48h: 67.9 W iopentol, 20.3 % compound A, 10.9 % others.

Example 8 (Comparative) lopentol Compound A (1 eqv., 10 g) was dissolved in an aqueous solution of KOH (1.0 eqv., 0.75 g) in water (1.0 volume/weight compound A, 10 ml). Glycidyl methyl ether (1.03 eqv., 1.21 g) was added to the stirred solution at 200C. The reaction mixture was stirred at 200C. After 24h and 48h, samples of 50y1 were taken, diluted in a solution of conc. HCl (50y1) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 57.0 % iopentol, 26.5 % compound A, 15.0 % others. Results (area-%) after 48h: 56.0 % iopentol, 20.3 % compound A, 16.1 * others.

Example 9 (Comparative) lopentol Compound A (1 eqv., 10 g) was dissolved in an aqueous solution of KOH (1.5 eqv., 1.13 g) in water (1.0 volume/weight compound A, 10 ml). 3-Chloro-l-methoxy-2propanol (1.03 eqv., 1.72 g) was added to the stirred solution at 200C. The reaction mixture was stirred at 200C. After 24h and 48h, samples of 50y1 were taken, diluted in a solution of conc. HCl (50y1) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 76.1 % iopentol, 19.3 * compound A, 4.2 % others.

Results (area-%) after 48h: 81.7 % iopentol, 11.9 % compound A, 6.1 % others, Example 10 (Comparative) Iopentol Compound A (1 eqv., 10 g) was dissolved in an aqueous solution of KOK (2.0 eqv., 1.50 g) in water (1.0 volume/weight compound A, 10 ml). 3-Chloro-l-methoxy-2propanol (1.03 eqv., 1.72 g) was added to the stirred solution at 200C. The reaction mixture was stirred at 200C. After 24h and 48h, samples of 50 l were taken, diluted in a solution of conc. HC1 (50y1) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 65 % iopentol, 20 % compound A, 16 % others.

Results (area-%) after 48h: 64 % iopentol, 20 % compound A, 16 % others.

Example 11 loversol N,N'-Bis(2,3-dihydroxypropyl)-5-glycolam triiodoisophthalamide (compound F) (1 eqv., 7.0 g) was dissolved in an aqueous solution of KOH (5.5 eqv., 2.83 g) in water (1.0 volume/weight compound F, 7 ml). Boric acid (3.5 eqv., 1.99 g) was added and the solution was stirred for 1-24h (preferably 18h) at 200C. 2-Chloro-lethanol (1.05 eqv., 0.78 g, 0.644 ml) was added to the stirred solution at 200C. The reaction mixture was stirred at 200C. After 24h and 48h, samples of 50 l were taken, diluted in a solution of conc. HCl (50 l) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 67.8 % ioversol, 12.8 % compound F, 19.4 8 others. Results (area-%) after 48h: 67.5 % ioversol, 11.1 % compound F, 21.4 % others.

Example 12 (Comparative) loversol Compound F (1 eqv., 7.0 g) was dissolved in an aqueous solution of KOH (2 eqv., 1.03 g) in water (1.0 volume/weight compound F, 7 ml). 2-Chloro-1-ethanol (1.05 eqv., 0.78 g, 0.644 ml) was added to the stirred solution at 200C. The reaction mixture was stirred at 200C. After 24h and 48h, samples of 50y1 were taken, diluted in a solution of conc. HCl (50 l) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24h: 39.2 % ioversol, 23.4 % compound F, 37.4 % others.

Results (area-%) after 48h: 37.6 % ioversol, 23.2 compound F, 39.2 % others.

Example 13 lodixanol Compound A (1 eqv., 100g) was dissolved in an aqueous solution of KOH (3.0 eqv., 22.53g) in water (0.9 volume/ weight Compound A, 90 ml). Boric acid (2.0 eqv., 16.55g) was added and the solution was stirred for 1 to 24 hours, preferably 18 hours, at 100C. The starting pH = 12.93. Epichlorohydrin (0.57 eqv., 7.046g) was added to the stirred solution at IOOC. The reaction mixture was stirred at 10 C and the pH was stabilized in the range 12.6-13. After 24 hours and 48 hours samples of 50 l were taken, diluted in a solution of conc. HCl (50 p1) in water (14 ml), and analyzed by RP-18 HPLC.

Results (area-%) after 24 hours: 80.5 Iodixanol, 6.9% Compound A, 7.5% Iohexol, 5.1% others. Results (area-%) after 48 hours: 83.4% Iodixanol, 2.5% Compound A, 8.9 Iohexol, 5.2% others.

Example 14 Iodixanol Compound A (1 eqv., 100g) was dissolved in an aqueous solution of borax K2BgO74H20 (2.0 B-eqv., 20.45g) in water (1.0 volume/weight Compound A, 100 ml). KOH (2.0 eqv., 15.02g) was added and the solution was stirred for 1 to 24 hours, preferably 18 hours, at 100C. Starting pH = 12.86. Epichlorohydrin (0.55 eqv., 6. 80g) was added to the stirred solution at 10 C. The reaction mixture was stirred at 100C and the pH was stabilized in the range 12.6-13 by addition of small amounts of boric acid or KOH. After 24 hours and 48 hours, samples of 50 l were taken, diluted in a solution of conc. HCl (50 l) in water (14 ml), and analyzed by RP-18 HPLC.

Results (area-%) after 24 hours: 80. 6% Iodixanol, 8.9% Compound A, 6. 1% Iohexol, 4.4% others. Results (area-%) after 48 hours: 83.4% Iodixanol, 4. 7W Compound A, 7.1% Iohexol, 4.8% others.

Example 15 lodixanol Compound A (1 eqv., 100g) was dissolved in an aqueous solution of potassium metaborate KBO2. H20 (2.0 B-eqv., 26.75g) in water (1.0 volume/weight Compound A, 100 ml).

KOH (1.0 eqv., 7.51g or less) was added to the stirred solution until the pH was stabilized in the range 12.613. The solution was stirred 1 to 24 hours, preferably 18 hours, at 100C. Starting pH = 12.71.

Epichlorohydrin (0.55 eqv., 6.80g) was added to the stirred solution at 10 C. The reaction mixture was stirred at 100C and the pH was stabilized in the range 12.6-13 by addition of small amounts of boric acid or KOH. After 24 hours and 48 hours, samples of 50 l were taken, diluted in a solution of conc. HCl (50 pl) in water (14 ml), and analyzed by RP-18 HPLC. Results (area-%) after 24 hours: 79.8 Iodixanol, 8.7% Compound A, 6.8 % Iohexol, 4.7% others. Results (area-%) after 48 hours: 83.3% Iodixanol, 3.8% Compound A, 7,8% Iohexol, 5.1% others.

Example 16 (Comparative) Iodixanol Compound A (1 eqv., 100g) was dissolved in an aqueous solution of sodium hydroxide (1.2 eqv., 6.43g) in water (3.0 volume/weight Compound A, 300 ml). The solution was stirred 1 to 24 hours, preferably 18 hours, at 250C.

Epichlorohydrin (0.5 eqv., 6.181g) was added to the stirred solution at 250C and stirring continued. After 24 hours 150 l were taken, diluted in a solution of conc. HC1 (50 Fl) in water (14 ml), and analyzed by RP18 HPLC. Results (area-%) after 24 hours: 49.1% Iodixanol, 25. 1% Compound A, 9.1% Iohexol, 16.7% others.

Claims (7)

1. Claims 1. A process for N-alkylation of a substrate to yield an N-alkyl group containing product which comprises an alkylatable moiety in said N-alkyl group, said process comprising reacting said substrate with an alkylating agent containing an alkyl at able group or a precursor therefor, characterised in that said substrate and/or said alkylating agent is reacted previously or simultaneously with a boron oxyacid, and in that said process further comprises deprotecting boron protected groups and optionally recovering said product.
2. 2. A process as claimed in claim 1 for the Nalkylation of a n,n+1 or n,n+2 bishydroxyalkylaminocarbonyl -acylanilide, which process comprises reacting a n,n+l or n,n+2 bishydroxyalkylaminocarbonyl-acylanilide with a boron oxyacid and simultaneously or subsequently with an alkylating agent, subsequently deprotecting boron protected diol groups, and optionally recovering the Nalkylated bishydroxyalkylaminocarbonyl-acylanilide.
3. 3. A process as claimed in claim 1 or claim 2 for Nbishydroxyalkylation of an organic compound having a primary or secondary amino (or amido) group, said process comprising reacting an organic compound having a primary or secondary amino (or amido) group with a n,n+1 or n,n+2 bishydroxyalkylating agent in the presence of a boron oxyacid, subsequently deprotecting boron protected diol groups, and optionally recovering the Nbishydroxyalkylated organic compound,
4. 4. A process for the N-alkylation of a 1-amino-2,3- propanediol or 2-amino-1,3-propanediol using an alkylating agent, characterised in that said l-amino2,3-propanediol or 2-amino-1,3-propanediol is contacted with a boron oxyacid diol protecting agent before or simultaneously with contact with said alkylating agent.
5. 5. A process for the alkylation of the acylated nitrogen of a n,n+1 or n,n+2 diol substituted N-acylanilide using an alkylating agent, characterised in that said n,n+l or n,n+2 diol substituted N-acyl-anilide is contacted with a boron oxyacid diol protecting agent before or simultaneously with contact with said alkylating agent.
6. 6. A process as claimed in any one of claims 1 to 5 wherein said boron oxyacid is boric acid or a borate.
7. 7. A process as claimed in any one of claims 1 to 6 wherein said alkylating agent is an oxirane or an n,n+2 or n,n+1 diol.