NOVEL SYNTHETIC METHODS FOR NON-IONIC RADIOGRAPHIC CONTRAST MEDIA

BACKGROUND OF THE INVENTION Field of the Invention

There is a great need for radiographic contrast media which are both non-toxic and economically produced, employing inexpensive and readily available intermediates and reagents, with increasing use of the larger doses demanded by new imaging methods, the incidence of unto¬ ward effects caused by ionic contrast media has become a serious concern. Newer, non-ionic radiographic contrast media are less toxic, but their high cost is a substan¬ tial deterrent to their generalized use and makes them a major factor in the expense of the diagnostic process. Development of low cost, non-ionic radiographic media has, therefore, become a particularly challenging area of synthetic organic chemistry.

Radiographic contrast media should be water soluble, non-toxic, and have a high iodine content. Most of these non-ionic radiographic contrast media are aro¬ matic amides with one or more amino groups, having poly- hydroxy, lower aliphatic alkyl and acyl s-.-bgroups bonded to nitrogen, with annular carboxamide and amino groups. The final synthetic product contains a large number of functionalities in close spatial relationships. An expensive moiety, the triiodinated benzene ring, pro¬ vides for a major portion of the weight of the product; once the aromatic ring has been iodinated, even small deviations from the theoretical yield can greatly affect the economics of the process. Also contributing to the cost are the water solubilizing functionalities, typic¬ ally several hydrox alkylamines, attached as amides. These amines include serinol, l-amino-2,3-propanediol, N-methyl l-amino-2,3-propanediol, and aminotetritols; and are all expensive.

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In developing improved products it is essential that processes allow for substantial flexibility in the way solubilizing moieties are attached and/or generated on the aromatic ring. In addition, synthesis should provide for high yield, in all steps of the synthetic process. Description of the Prior Art

German OS 2,658,300 describes the preparation of contrast media. See also U.S. Patent No. 3,701,771 as illustrative of the preparation of contrast media.

Also of interest are U.S. Patent Nos. 4,001,323; 4,021,481 and 4,278,654, as well as UK Patent Nos. 1,321,591 and 2,031,405; and Dutch Application No. 79/05166.

SUMMARY OF THE INVENTION Procedures for preparing non-ionic radiographic contrast media and novel compounds prepared thereby are provided. The procedures involve at least one of the following steps with a symmetrical triiodobenzamide, where the remaining positions are substituted by a non- oxo-carbonyl group (carboxy carbonyl) or an amino group. The steps: (1) acylation with imide formation and, op¬ tionally, peracylation of amino nitrogen; (2) substitu¬ tion with an olefinically unsaturated compound—alkyla- tion or acryloylation—and subsequent oxidation to a diol; (3) anilide substitution with a 1'-substituted methyloxirane; and (4) alkylation of imide nitrogen with alkyl groups having a reactive leaving group. In addi¬ tion to the above reactions, additional steps may be in¬ volved, which are amide or bis-amide formation with masked hydroxyalkyl amines or diamines, amide formation with ammonia or alkyla ines, formation of acyl halides, etc. The subject invention involves the employment of inexpensive intermediates which can act as polyolamine precursors, particularly olefins, oxiranes, or masked polyols, either substituting at imide or anilide nitrogen or with formation of amides, or the use of acrylic acids

as an intermediate to glyceric acids. The resulting products are water soluble, may have low osmolality, low viscosity and low toxicity and can find a variety of uses, particularly as radiographic contrast media with clinically acceptable properties.

DESCRIPTION OF THE SPECIFIC ^' EMBODIMENTS

Synthetic strategies are provided involving individual steps, including individual novel synthetic procedures, to produce substituted nitrogen atoms, where the nitrogen atoms are associated with aroyl amides or amine nitrogen atoms bonded to annular carbon atoms of an aromatic ring, normally a benzene ring. The aromatic rings are highly substituted in that there are no hydro¬ gen atoms. The compounds are mono- or dibenzamides, where the rings are symmetrically triiodinated and the remaining positions are substituted with amino groups to provided phenyl amines having anilino characteristics or carboxamide groups, particularly isophthaldiamide com¬ pounds. The synthetic strategies will usually involve minimizing or avoiding the use of polyhydroxyamines, by employing such glycol precursors as olefins and oxiranes. In addition, acylation is used to achieve a variety of purposes, including activation of nitrogen atoms for alkylation, amide nitrogen atoms by imide formation and aniline nitrogen atoms by anilide formation, and as block¬ ing groups to permit selective substitution, particularly alkylation.

Alternative approaches may involve the use of allylamines and amidation with aroyl halides to form amides, which may be subsequently oxidized. Alternative¬ ly, nitrogen atoms may be acylated with unsaturated ali¬ phatic acids, e.g., acryloyl acid, followed by oxidation to the diol. A novel method for preparing acyl halides in the presence of the other annular substituents is pro- vided.

The subject compounds will have at least 4 oxy groups, usually at least 5 and may have from 6 to 10 oxy

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groups as the final monomeric product, with up to 14 oxy groups when dimeric.

The radiographic contrast media and other pro¬ ducts may have from one to two aromatic carboxamide groups. The dimeric products will have the carboxamide nitrogen atoms joined by a bond, e.g. hydrazine, or an alkylene group of from 2 to 4 carbon atoms having from 0 to 2 oxy groups, where the remaining valences of the two nitrogen atoms may be satisfied by hydrogen or from 0 to 2, usu- ally 0 to 1, hydroxyalkyl group of from 2 to 4, usually 2 to 3 carbon atoms and from 1 to 3, usually 1 to 2 hy- droxyl groups per alkyl group.

Various strategies will be provided for pro¬ ducing the monomeric and dimeric compounds. An i port- ant strategy involves the use of imides and anilides for activating nitrogen atoms for alkylation. This strategy may be used by itself or in combination with other stra¬ tegies, such as acylation with acrylic acid, which may serve as a precursor to glyceric acid and analogs there- of. In some instances, substituted alkyl oxiranes may be employed as precursors to N-polyhydroxyalkyl substit- uents. In addition, strategies may involve the prepara¬ tion of acyl halides as intermediates, which will involve preventing undesired side reactions involving other sub- stituents present on the ring. For example, amino groups with benzoyl halides, as distinct from polycarboxylic acid compounds, should be protected by persubstitution. Also, hydroxyl groups should be protected by ether or ester formation. One synthetic s-trategy involves the following process for preparing monomeric carboxamides, which pro¬ cess will involve one of the following reaction sequences:

1. (H O R(C0H _o ) + AWX ~> ((AW) N) R(COHWA)

2a. ((AW) 4..N)n R(CONHWA)m + B ^L * _ς ^Λ -i ^J (A H)n R(CONH2„)m

2b. ((AW)„--N)n R(CONHWA)m + B ^L * ^J (AWNH)n R(CONHWA)m

3a. (AWNH)n R(C0NH-_-,)m + DY + B' -> (AWN(D))n R(C0NHz) 3b. (AWNH) _n R(CONHWA) + DY + B' -» ^• (AWN(D)) R(C0N(D)WA) _m

4. (AWN(I»)n R(C0N(D)WA)m + B -> (AWN(D))n R(CONH(D))m

(2a and 3a or 2b and 3b will be employed, while 4 is optional with the b sequence.)

The symbols are defined as follows: R is a substituted phenyl group with three symmetrically substituted iodine atoms, at least one carboxamide and the remaining two positions substituted with amino, carboxamido or nitrogen substituted deriva¬ tives thereof; - n + m equals 3, while m is 1 to 3, preferably

1 to 2 and n is 0 to 2, preferably 1 to 2;

A is an organic group, which will vary with W and whether it is to be retained or removed, where W is carboxyl, A will be an aliphatic group of from 1 to 4, usually 1 to 3 carbon atoms, preferably 1 to 2 carbon atoms, which may be saturated or unsaturated, usually ethylenic unsaturation, substituted or unsubstituted, particularly oxy substituted, moie particularly, pro¬ tected oxy, such as acyloxy of from 2 to 3 carbon atoms, or alkoxy, including acetals and ketals, with oxo groups of from 1 to 4, usually 1 to 3, carbon atoms; where W is inorganic, A may also be aromatic of from 6 to 10 carbon ^' atoms, unsubstituted or substituted e.g. alkyl, halo, etc.; W is an acyl functionality, either organic or inorganic, including carbonyl and sulfonyl;

X is a group which activates the carbonyl for substitution on the amide nitrogen and includes halo, normally chloro, an acyl group, which may form a symme¬ trical or asymmetrical anhydride, e.g., tert.-butyloxy- carbonyl, hydroxyl, which may be activated with an ap¬ propriate carbodiimide, azido, or the like;

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DY is an alkylating agent, where D is a lower aliphatic group of from 1 to 4, usually 1 to 3 carbon atoms, which may be saturated or unsaturated, usually ethylenic, substituted or unsubstituted, particularly oxy substituted, more particularly, protected oxy, such as acyloxy of from 2 to 3 carbon atoms, or alkoxy,. in¬ cluding acetals and ketals with oxo groups of from 1 to 4, usually 1 to 3, carbon atoms; and

Y is a leaving group which may be displaced by the-nitrogen of the imide, and may include halo of atomic number of at least 17, inorganic ester, e.g., sulfate, sulfonate, phosphonate, etc., or the like;

B, B ¹ and B" are basic compounds which will vary with the reactions involved; and S is a non-protic solvent, while SH is a pro- tic solvent, which will vary according to the reactions occurring at substituent sites. n will be at least 1 in reactions 2b and 3b.

It should be appreciated that the above list is not exhaustive of the-variety of groups which may be used as reactants ^' or of the permissible variation in reactions. Rather, other reaction sequences are per¬ mitted as well as other reactants.

For dimeric products the procedure will be similar to monomeric products, but differ in certain details. The carboxylic acid or ester will be acylated and/or alkylated prior to forming the dimeric carboxamide with an activated carboxy group, e.g. an acyl chloride. The reaction ^r~ :ience will vary as follows,, with - the same symbols previ γ -indicated having the same meaning:

5. (H 2-,N. .CONH 2.,) m-, COG + AWX ->

((A.., ₂ N) _nl R(CONHWA) _ml COG 6a. ((AW) ₂ N) _nl R(CONHWA) _ml COG + B → ^S - ^H (AWNH) _nl R(CONH ₂ ) _ml COG 6b. ((AW) ₂ N) _nl R(CONHWA) _ml COG + B - ^S

(AW? ^' - R( CONHWA ) , COG m ^x

7a . (AWNH . :SNH ₂ ) _ffil COG + DX + _. B ^f

(AWNE - ( CONH ₂ ) _ml COG

7b. (AWNH)„n ₁ R(CONHWA)m, COG + DX + B' ^■ _*

(AWN(D)) _nl R(C0N(D)WA) _m2 COG

8. (AWND) _n2 R(CON(D)WA) _ml COG + ZX ->

(AWND) _nl R(CON(D)WA) _ COX

9. (AWND) n,~R(CON(D) ^y WA) m ¹ , COX + HpD _A qNJNDqHp

((AWND) _nl R(CON(D)WA) _ml CON(D ) ) ₂ Q 10. ((AWND) _nl R(CON(D)WA) _ml CON(D*)) ₂ Q + B (AWN(D) _nl R(CONH(D) _ml CON(D*)) ₂ Q (6a and 7a or 6b and 7b will employed, while 10 is op- tional)

The symbols not previously defined are defined as follows: n ¹ + m ¹ equals 2, while n ¹ is 1 to 2 and m ¹ is 0 to 1; G is an hydroxyl, alkoxyl or oxy salt, e.g.

ONa, varying with the conditions of the reaction;

ZX intends a compound capable of activating a carboxyl group, such as an acyl halide, a chlorinating agent, e.g. PC1 ₅ or S0C1 ₂ , carbodiimide, etc.; D includes hydrogen and the definition for D; is a bond or alkylene group of from 2 to 4 carbon atoms and from 0 to 2 hydroxyl groups; p + q equals 2, where p is 1 to 2 and q is 0 to 1, and the p's may be the same or different. The particular reagents will be chosen with regard to their role in the synthetic strategy, as well as their presence or absence in the final product. Where the reagent is to be retained in-the final product, the selection will be much more restrictive. Where the reagent has only a transient existence during the syn¬ thetic procedure in that it is introduced at one step and removed at a subsequent step, selection, will be less restricted and more directed to the reagents cost and its effect on facilitating the synthesis. Alkylating groups will normally be permanent and while subject to modification, e.g., oxidation, hydrolysis, etc., will be retained with the final product. By way of contrast,

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acyl groups may or may not be retained in the final pro¬ duct. Where retained in the final product, the acyl group will normally be a carboxyl. Where the acyl group has only a transient presence, it may be either carboxyl or sulfonyl, preferably carboxyl. Usually, sulfonyls will be involved with imide formation rather than amide formation.

A prime function of the subject invention is to have an economic synthesis. Therefore, those react- ants or substituents that do not appear in the final product will be selected for low cost and ready avail¬ ability and for their effect on yield and processing costs. To that extent, certain groups will be preferred over others. For example, for a removable acyl group of an imide, the acetyl or methylsulfonyl groups will be preferred, particularly as acetyl chloride, acetic an¬ hydride or methylsulfonyl chloride. For aliphatic substitution, methyl and ethyl chlorides, bromides or sulfates are preferred as alkylating agents, and 2-pro- penyl, 2-butenyl and 2-buten-4-hydroxyl (the hydroxyl group is protected) are preferred for intermediates to polyhydroxylated alkyl substituents.

Particular intermediates-involved in the sub¬ ject invention may have the following formula: COG*

wherein: p and q are the same or different and are 0 or 1, preferably p is 0, while G is ammo, chloro, allylamino, acryl- oxylamino, aryl of from 2 to 3 carbon atoms, hydroxyl, alkoxy of from 1 to 6 carbon atoms or an oxy salt. The compound of the above formula will be designated as I. For the di er, G is other than amino or substituted amino.

* . Upon acylation of compound I, where G is amino, the following product will be obtained:

CONHWV

wherein: W is CO or S0 ₂ ; V is H, alkyl of from 1 to 6 carbon atoms, par¬ ticularly 1 to 3 carbon atoms, having 0 to 1 olefinic groups, or aryl of from 6 to 10 carbon atoms, which may be unsubstituted or substituted, e.g. alkyl, halo, etc. E E and E are the same or different and are of the formula:

^• 0

0

-CNHWV or -N(WV) ₂

where there is an amino group bonded to an annular carbon atom, the amino group becomes diαcylated, while where there is.an amide nitrogen, the amide becomes monoacy- lated.

*

For the dimer, where G is not ammo, it will come within the definition of G. Compounds which may serve as starting materials or intermediates may come within the following formula:

COG

(VW) _s (J) _r N(CO) _p ((CCO0)) _gg >N(J) _r (WV) _s

I

wherein: - G is am o, allylamino, acryloylamino, acyl of from 2 to 3 carbon atoms, chloro, hydroxyl, alkoxy of from 1 to 6 carbon atoms or an oxy salt;

W is S0 ₂ or CO;

V is alkyl of from 1 to 3, preferably 1 to 2, carbon atoms having from 0 to 1 site of- olefinic unsatu- ration or from 0 to 1 hydroxy, masked hydroxy, e.g. acetoxy or ethoxy, when W is CO, or an organic radical - of from 1 to- 10 carbon atoms, when W is S0 ₂ ;

J is H, (WV), alkyl of from 1 to 2 carbon atoms, allyl, glycidyl or dihydroxypropyl; p and q are 0 or 1, r is 1 or 2, s is 0 or 1, and p+s and q+s are 1 or 2, where p and/or q are 1, J will usually be other than (VW); with the proviso that J is other than H when p and q are 0 and G is chloro.

Usually, there will be only one glycidyl per nitrogen atom. Also, J will usually be other than hydro¬ gen, when the associated symbol p or q is 0, and be hy¬ drogen or ^' alkyl when the associated symbol p or q is 1. Desirably, for an intermediate to polyhydroxylation there will be from 1 to 3 olefinic or glycidyl groups.

In the preparative procedure, the final product may have G replaced with G , where G ^' is 1,3- or 2,3- dihydroxy-2, or 1-propylamino or N-methyl derivative thereof or 2,3,4-trihydroxy or 1,3,4-trihydroxy-l or 2-butylamino.

Final products of interest will have the fol¬ lowing formula:

O P

wherein: t is 1 or 2; when t is 1, K is amino, alkylamino of from 1 to 2 carbon atoms, or hydroxyalkylamino of from 2 to 4 carbon atoms having from 1 to 3 hydroxyl groups; when t is 2, K is alkylenediamine of from 2 to 3 carbon atoms or N-polyhydroxyalkyl alkylene diamine; N-polyhydroxyalkyl is of from 3 to 4 carbon atoms and 2 to 3 hydroxyl groups and said alkylene is of from 2 to 3 carbon atoms;

W is CO;

V is alkyl of from 1 to 2 carbon atoms, oxy- alkyl of from 1 to 3, usually 1 to 2, carbon atoms having from 1 to 3, usually 1 to 2, oxy groups which are hy- droxy or methoxy;

J' is H, alkyl of from 1 to 2 carbon atoms, (W'V ) or hydroxyalkyl of from 2 to 4 carbon atoms and 1 to 3 hydroxyl groups, where the J' groups may be the same or different; p, q, s ^f and s" are 0 or 1, usually p+s" and q+s" will be 1; and • r' and r" are 1 or 2.

Usually, J' will be other than W'V when the associated p or q is 1, usually only one J' per nitrogen being polyhydroxyalkyl.

For the most part, the basic ring .structures will be 3,5-diamino-2,4,6-triiodobenzoic acid and 5- amino-2,4,6-triiodoisophthalic acid. The acid groups may be present as the acyl chloride, ester, salt, or

« amide, in the final product being the amide. In the intermediate compounds amide nitrogens will be substi¬ tuted with the following groups: which will be removed, acyl sulfonyl; e.g. methylsulfonyl, phenylsulfonyl and toluenesulfonyl; which may or may not be removed, acyl carboxyl, e.g. acetyl, hydroxyacetyl, masked hydroxy¬ acetyl, e.g. methoxyacetyl and acetoxyacetyl, acryloyl, glyceric acid, masked glyceric acid, e.g. acetonide of glyceric acid, 4-hydroxy-2-butenoic acid, masked 4-

hydroxy-2-butenoic acid, e.g. 4-acetoxy or 4-methoxy, and 2,3,4-trihydroxybutyric acid and masked derivatives thereof, e.g. acetoxy, methoxy and acetonide; which are not removed, methyl, ethyl, 2-hydroxyethyl, allyl, 1,3 and 2,3-dihydroxypropyl or the diacetoxy or acetonide, glycidyl, 3-hydroxymethylglycidyl or the 3-acetoxy or methoxy, l,3,4-trihydroxypropyl-2 or acetoxy and/or acetonide thereof, and 2,3,4-trihydroxybutyl or acetoxy and/or acetonide thereof. Depending upon the conditions, the various acyl groups may be selectively removed. The diacylated annular amino can be selectively transformed to a mono- acylated amino, while retaining the acyl group on the benzamide nitrogen. The mixed benzoyl acyl imide may be hydrolyzed to the benzamide, while retaining monoacyl substituents on the annular amines. This is relevant to the next stage, where selective substitution can be achieved, depending upon the nature of the nitrogen atoms and the substituents. Substitution can occur on the mixed imide and the mono-acylated annular amines, and does not occur under the selected conditions on the diacylated annular amines, nor on the benzamide. One can selectively and stepwise remove acyl groups and introduce nitrogen substituents to provide the desired product. For example, the following illustrative se¬ quences may be performed:

TIB

TIB

(TIB) intends symmetrical triiodo benzene, with the remaining annular carbons being substituted by the groups set forth. The other symbols which are indi¬ cated have been defined previously.

In accordance with the above scheme, one can react all of the nitrogen atoms under mild conditions to produce substituted nitrogen atoms bonded to a sat¬ urated aliphatic carbon atom and thus provide for mono- substituted benzoylamides, as well as mono-substituted anilide nitrogen.

A second illustrative procedure is provided as follows:

TIB

4- A'WCl )WA'

TIB

In the above illustration, all of the formulas have been defined except A' and D', which have the same definitions as A and D, respectively, but may differ from A and D, respectively, in the above sequence. Therefore, in accordance with the above sequence, one can provide for different nitrogen substitution on the benzamide nitrogen, as distinct from the anilide nitro¬ gen.

A third illustrative procedure is provided as follows:

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TIB

TIB

TIB M

with the symbols as defined previously, except for M which is a bond or alkylene bridge of from 2 to 3 carbon atoms. The starting materials for the monomeric com¬ pounds of the subject invention will be symmetrically substituted triiodo benzamides, having substituents at the 3 and 5 position, which are either carboxamide or amino, where from 0 to 2 of the nitrogen atoms may have aliphatic substituents, usually not more than one sub- ^' stituent, but there will be at least one nitrogen atom which has two hydrogen atoms.

The first step will be the acylation of the available nitrogen atoms. The acylation can be for activation of nitrogen for subsequent substitution or protection of nitrogen from subsequent substitution. Thus, the procedure will vary .depending upon the desired product. The procedure will also vary depending upon . the nature of acylating agent. As indicated previously, the three major types of acylating agents will be acyl halides, particularly acyl chlorides, e.g. carboxyl or sulfonyl, anhydrides, both symmetrical and asymmetrical,

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and carboxylic acids in combination with a carbodiimide. For acyl halides, acylation will normally occur under mild conditions in an inert polar medium, particularly an amide, e.g., dimethylacetamide or dimethylformamide, at concentrations which may be varied widely, generally being not less than about 0.01M and not more than about 1M, and temperatures in the range of about 0° to 40°C, more usually from about 0° to 30°C. The time will vary depending upon the concentration, . the nitrogen being acylated, the temperature, and the like. Normally, the time will be at least about 30min and not more than about 48hr, generally being at least about lhr and less than about 36hr. The ratio of the acylating agent may be varied widely, generally being at least stoichiometric, usually in about 1.5 mole excess, and not more than about 10 mole excess, usually not more than 5 mole excess.

For acylation with an anhydride, the anhydride may conveniently serve as a solvent, being in substantial molar excess, usually at least two-fold excess and as high as ten-fold excess or greater. Also included will be a mineral acid, particularly sulfuric acid, which may be present in from about 0.5 to 25 volume percent, more usually from about 1 to 20 volume percent, the volume percent varying depending upon the ratio of the anhydride to the benzamide. Temperatures that will be employed will generally range from 0° to 90°C, more usually from about 10° to 80°C, and times may vary from about O.lhr to 6hr.

The mode of alkylation will vary with the alkylating agent and the ^" desirability of simultaneous removal of acyl groups. Thus, by the conditions employed one can select which nitrogen atoms will be substituted with an aliphatic group. The aliphatic groups will generally be lower alkyl, methyl or ethyl, alkenyl, particularly propenyl or -2-butenyl, or substituted alkyl, particularly oxy substituted alkyl, where the oxy group is protected by an ether or an ester linkage, e.g., oxiranyl, acetonide or acetoxy.

O PI

Alkyl halides will normally involve the use of an inert polar solvent, capable of dissolving the benzamide and the alkyl halide and maintaining the com¬ pounds in solution at the reaction temperature, which will generally be in the range of about 0° to 40°, more usually in the range of about 10° to 30°C. Particularly convenient as a solvent is dimethyl sulfoxide. A mild base will be employed, a non-hydroxylic base, for exam¬ ple, potassium carbonate, sodium carbonate, or other convenient base, providing a pH in aqueous medium of about 10 to 13, preferably about 11 to 13, or hydroxylic. The amount of base will generally be from about 0.1 to 1 mole ratio to alkylating agent. The time will be at least about 2hr and not more than about 72hr, the reac- tion being monitored to determine whether no further reaction is occurring.

For alkenyl halides the conditions will be substantially the same as for the alkyl halide, except that lower temperatures may be used, generally not ex- ceeding 65°C, usually not exceeding about 60°C, ranging from about 20° to 65°C, more usually from about 30° to 60°C.

With substituted alkyloxiranes, the reaction will be carried out in the presence of base as described for allylation at mildly elevated temperatures, about 35-100°C, in a hydroxylic solvent, either mono- or di- hydroxy, particularly glycols of from 2 to 4 carbon atoms.

Alternatively, the imide salt may be obtained by employing a metal hydride, particularly an alkali metal hydride, e.g., sodium hydride, in at least stoi- chiometric and preferably excess amounts, usually not greater than about 5M excess in an ine.rt polar solvent, e.g., an N,N-dialkylamide, under mild conditions in conjunction with an aliphatic halide. Single or multiple additions of the hydride and halide may be made. -The temperature may generally range from about 20° to 60°C and periods of time may extend to one week or more.

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The halide will generally be at least in stoichiometric amount and usually in substantial excess, frequently at least about 2M excess and may be 15M excess or greater. To enhance activity where a chloride is em- ployed, a small amount of a tetraalkylammonium bromide or iodide salt may be employed, which tends to accelerate the reaction. The amount of the ammonium salt will generally be catalytic, generally ranging from about 1 to 20 mole percent of the halide. Where monoacylated, the acyl -groups may be removed preferentially from imide nitrogen as distinct from anilide nitrogen. A wide variety of conditions may be employed for removing the imide acyl group, in¬ cluding an aqueous or non-aqueous polar organic solvent containing an alkali metal hydroxide of from about 0.1 to 1 Normal, e.g., aqueous dioxane sodium hydroxide; sodium methoxide in methanol, powdered potassium hydrox¬ ide in dimeth lacetamide, or the like. Temperatures will generally range from about 20° to 50°C and the base will normally be in excess although in some in¬ stances, e.g., methoxide, catalytic ^' amounts may suffice.

In one synthetic strategy, a carboxylic acid or salt is maintained and the amide produced late in the synthetic process. This will be true particularly where one is concerned wit-iϊ dimer formation. In order to form the amide, one will prepare the carboxylic acid chloride, using a carboxylic acid chloride-forming agent, usually an inorganic or organic acid halide. These com¬ pounds include thionyl chloride, which is preferred, phosgene, oxalyl chloride, sulfuryl ^' chloride, or the like. The carboxylic acid group may be in the form of the acid, mixed anhydride, or salt. The anilide nitro¬ gens may be persubstituted, having from 1 to 2 acyl sub¬ stituents or 0 to 1 alkyl substituents depending upon the manner of formation of the acyl halide. Any oxy groups should be protected from reaction with the halogenating agent.

The reaction may be carried out under mild conditions, generally below about 100°C, either in an inert solvent or employing the halogenating agent as the solvent, and using an excess of the halogenating agent, conveniently not more than about a two-fold excess. After completion of the reaction, the acyl halide may be separated from the spent halogenating agent and unreacted halogenating agent by distillation, solvent extraction, or the like and"may be used directly without further purification for reaction with an amine to form the amide.

For the dimeric product, the reaction of the acyl halide with the diamine will be carried out in an inert polar organic solvent, e.g., N,N-dialkylated amide, under mild conditions, e.g., room temperature, the reaction allowed to proceed, followed by isolation of the diamide. The product may then be treated substantially in the same manner as the analogous monomeric product, whereby acyl groups may be removed and replaced with alkyl groups, olefins may be oxidized to glycols, and/or substituted alkyl oxiranes may be hydrolyzed and the like.

The workup of the various products at the intermediate stages as well as the final product can employ conventional ways, such as solvent extraction, chromatography, crystallization, or other conventional technique. When hydroxyl groups are present or intro¬ duced, ^■ the available hydroxyl groups may be derivatized by O-acylation, e.g., 0-acetylation, or ketal formation, e.g., acetonide, using acetone or acetone ketal, e.g., methyl or ethyl ketal. The product can usually be iso¬ lated in pure form by extraction from the aqueous medium with a substantially water immiscible solvent, chloro¬ form, washing the organic layer and removing the solv- ent. The product may then be recrystallized from an hydroxylic solvent of low water solubility, e.g., higher alcohol. The O-substituents may be removed by acid

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hydrolysis, using, for example, an acid ion exchange resin in the crystallization'solvent involving alcohol exchange.

The following examples are offered by way of illustration and not by way of limitation:

EXPERIMENTAL EXAMPLE IA A. N,N'-bis-allyl 5-amino-2,4,6-triiodoisophthaldiamide ill A solution of 5-amino-2,4,6-triiodoisophthaloyl dichloride (1) (45.0g, 76mMoles) in 100ml freshly dis¬ tilled N,N-dimethylacetamide (DMA) was cooled to 5°C in an ice bath, and potassium carbonate (21,Og, 152 mMoles) was added. Allylamine (13.8g, 242mMoles) was added over 10 minutes. After most of the heat of the reaction was dissipated, the mixture was removed from the ice batch and stirred overnight at room temperature.

The reaction mixture was poured into an ice water slurry (1:1, 600ml) with vigorous mechanical stir- ring. The precipitate was filtered off, washed to neu¬ tral pH with water (6 x 150ml), and dried at 0.1mm Hg and 40°C over KOH pellets to yield a white solid, N,N'- bis-allyl 5-amino-2,4,6-triiodoisophthaldiamide (2), 50.lg (yield 98%). B. N,N'-bis-allyl 5-acrylamido-2,4,6-triiodoisophthal- diamide (3)

To an ice-cold solution of (2) (42.Og, δδmMoles) in 140ml distilled DMA, was added distilled acryloyl chloride (11.93g, 132mMoles) over a ten-minute period. The mixture was removed from the ice bath and stirred at room temperature for 16 hours.

The produce was isolated by pouring the reac¬ tion mixture into ice water (1.5L), with _. mechanical stirring. The mixture was filtered, the precipitate washed with water (4 x 200ml), and dried at 0.1mm Hg at 45°C overnight, to produce a white solid, N,N'-bis-allyl

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5-acrylamido-2 _Λ 4,6-triiodoisophthaldiamide (3) (45.0g, yield 98%).

C. N,N'-bis-(2,3-dihydroxypropyl) 5-glyceramido-2,4,6- triiodoisophthaldiamide (4) N,N'-bis-allyl 5-acrylamido-2,4,6-triiodoisoph- thaldiamide (3) (5.0g, 7.23mMoles), tetrahydrofuran (25ml free of stabilizers), water (5ml), t.-butyl hydro- peroxide (70% solution, 5.63g, 43.4mMoles), tetraethyl- ammonium acetate tetrahydrate (.377g. 1. 5mMoles) and osmium tetroxide (.018g, .0723mMoles) were combined in a flask. The mixture was kept at 50°C in an oil bath for 10 hours.

After cooling in an ice bath, sodium bisulfite (10% solution, 4.8mMoles) was added and the mixture dried and extracted wit 75 methanol/25 tetrahydrofuran. The insoluble salts were filtered off and the solvents removed (4.85g, 97% yield) to give a brown solid of N,N'-bis-(2,3-dihydroxypropyl) 5-glyceramido-2,4,6-tri- iodoisophthaldiamide (4), which was further purified by crystallization from octanol/water.

EXAMPLE IB A. N,N'-bis-allyl 5-(N"-methyl acrylamido)-2,4,6-tri- iodoisophthaldiamide (5)

N,N'-bis-allyl 5-acrylamido-2,4,6-triiodoisoph- -thaldiamide (3) (Example IA) (20.Og, 29mMoles) was added to distilled dimethyl sulfoxide (60ml). The mixture was warmed to 60°C, allowed to cool to room temperature, and solid potassium carbonate (6.0g, 43mMoles) was added. The mixture was cooled to 15°C in an ice bath, and fresh- ly distilled methyl iodide (7.38g, 52mMoles) was added over a ten-minute period.

After 15hrs stirring at room temperature the solution was poured into ice water (1:2, 500ml) and the precipitated solid filtered off, washed with water (4 x 200ml) and dried in vacuo (0.1mm Hg) over NaOH pellets at 45°C to give N _r N'-bis-allyl 5-(N"-methyl acrylamido)- 2,4,6-triiodoisophthaldiamide (5) (19.0g, yield 93%).

B. N,N'-bis-(2,3-dihydroxypropyl) 5-(N"-methyl glycer- amido)-2, ,6-triiodoisophthaldiamide (6)

In a 1L flask were combined N,N'-bis-allyl 5-(N"-methyl aery1amido)-2,4,6-triiodoisophthaldiamide (5) (50.0g, 71mMoles), acetone (400ml), water (75ml), potassium acetate (1.40g, 14.2mMoles), t.-butyl hydro- peroxide (70%, 46.4g, 355mMoles) and osmium tetroxide (0.180g, 0.71mMoles, as a solution in 8.27ml H ₂ 0). The mixture was allowed to stir 22 hours at room temperature. The reaction mixture was diluted with 500ml water and extracted with ethyl acetate (3 x 500ml).

The aqueous layer was evaporated, redissolved in water, deionizεd with a mixed bed ion exchange resin (A berlite), and the water removed to give 51.Og (95% yield by TLC) of N,N'-bis-(2' ,3'-dihydroxypropyl) 5-(N"- methyl glyceramido)-2,4,6-triiodoisophthaldiamide (6), which was further recrystallized from n-butanol.

EXAMPLE IC

A. N,N'-bis-allyl 5-(methylamino)-2,4,6-triiodoisoph- thaldiamide (8)

A solution of 5-(methylamino)-2,4,6-triiodo- isophthaldioyl dichloride (7) (130.0g, 213mMoles), in 300ml distilled DMA was cooled in an ice bath to 5°C, and dry potassium carbonate (58.46g, 426mMoles) was added. Allylamine (36.5g, 639mMoles) was added dropwise over 40 minutes. The reaction mixture was stirred at room temperature overnight. ^■

The product was isolated by pouring the solu¬ tion into stirred ice water (1:3, 2L), filtered, and washed with H ₂ 0 (3.5-4L). The product was dried over P ₂ O ₅ /0.5mm Hg/50°C/6 hours to obtain N,N"-bis-allyl 5-(methylamino)-2,4,6-triiodoisophthaldiamide (8) (129.07g, yield 93%).

B. N,N'-bis-allyl 5-(N"-methyl acrylamido)-2,4,6-tri- iodoisophthaldiamide (5)

In a 1L flask were combined N,N'-bis-allyl 5~(methylammo)-2,4,6-triiodoisophthaldiamide (8) (120g,

184mMoles) and freshly distilled DMA (350ml). The solu¬ tion was cooled in an ice bath, and distilled acryloyl chloride (23.11g _r 255mMoles) was added over ten minutes. The reaction proceeded for 8 hours at room temperature, when TLC (silica, 95% CHCl ₃ /5%MeOH) indicated exclusive conversion to a product.

The solution was poured into ice water (1:1, 2L), with vigorous mechanical stirring, followed by filtration of the precipitated solid, which was washed to neutral pH with water (5 x 400ml) and dried in vacuo (0.25mm Hg) at 50°C over NaOH pellets to obtain N,N'- bis-allyl 5-(N"-methyl acrylamido)-2,4,6-triiodoisoph- thaldiamide (5) (122.45g, 98% yield) .

The product was purified by recrystallization from tetrahydrofuran and methanol. One hundred grams of crude solid gave 4 crops of white crystals (yield 85%). By TLC (95 chloroform/5 methanol) Rf (8): 0.77; Rf (5): 0.62. The product is identical to that obtained in Example IB (5).

EXAMPLE ID

A. 5-amino-2,4,6-triiodoisophthaldiamide (9)

To a solution of 5-amino-2,4,6-triiodoisoph- thaloyl dichloride (1) (15.0g, 25mMoles) in 50ml dis¬ tilled N,N-dimethylacetamide in a 250ml Parr pressure bomb was added anhydrous ammonia (3.5g, 206mM) in 20ml DMA and cooled in an ice bath. After 12 hours at 40°C the excess ammonia was vented and the bomb opened. ^'

The bomb was warmed at 55°C for.1 hour and -the reaction mixture poured into a mechanically-stirred slurry of brine:ice:IN HC1 (100ml:100g:25ml) . The pro¬ duct was filtered, washed with H ₂ 0 (3 x 50ml), saturated aqueous sodium bicarbonate (25ml), H ₂ 0 (3 x 75ml), and dried overnight at 40°C in vacuo over potassium hydroxide ^• pellets to yield 5-amino-2,4,6-triiodoisophthaldiamide (9). TLC: (80% CHCl ₃ /20% MeOH) Rf: (9); 0.51.

B. 5-acrylamido-2,4,6-triiodoisophthaldiamide (10)

A suspension of 5-amino-2,4,6-triiodoisoph- thaldiamide (9) (20.0g, 36mMoles) in DMA (90ml) was cooled in an ice bath, and distilled acryloyl chloride (6.5g, 68mMoles) was added over a three minute period. The reaction proceeded at room temperature for 24 hours, and then was poured into a slurry of ice water (1:3, 650ml), with mechanical stirring. The precipitate was filtered off, washed to neutral pH with water (100ml x 6), dried in vacuo overnight at 0.1mm Hg/58°C over po¬ tassium hydroxide pellets, to give 5-acrylamido-2,4,6- triiodoisophthaldiamide (10) (19.20g, 87.5% yield). TLC: (80% CHCl ₃ /20% MeOH) Rf (9): 0.51; Rf (10): 0.40.

C. 5-(N-methyl acrylamido)-2,4,6-triiodoisophthaldi- amide (11)

A solution of 5-acrylamido-2,4,6-triiodoisoph- thaldia ide (10) (17.0g, 28mMoles) in distilled dimethyl sulfoxide (125ml) was mixed with potassium carbonate (5.8g, 42mMoles) and the mixture cooled to 15-20°C in an ice bath. Methyl iodide (7.95g, 56mMoles) was then added over a three-minute period. The mixture was re¬ moved from the ice bath. After 24 hours at ambient temperature, the product was isolated by pouring the reaction mixture into 700ml ice:brine (1:1). The pre- cipitate was filtered off, washed with water (5 x 50ml), and dried in vacuo at 60°C and 0.3mm Hg over potassium hydroxide pellets to give 5-(N"-methyl acrylamido)- 2,4,6-triiodoisophthaldiamide (11) (15.7g, 90% yield). TLC: (80% CHCl ₃ /20% MeOH):Rf (10): 0.52; Rf. (11) 0.63. D-. N,N'-bis-acetyl 5-(N"-methyl acrylamido)-2,4,6-tri- iodoisophthaldiamide (12)

A stirred suspension of 5-(N"-methyl acryl- amido)-2,4,6-triiodoisophthaldiamide (11) (6.25g, lOmMoles) in acetic anhydride (18ml, 190mMoles) was cooled in an ice bath. Concentrated sulfuric acid (2ml) was added dropwise over a three minute period. After 6 hours at room temperature, the solution was poured into

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a slurry of ice/brine (1:1, 400ml). The precipitate was filtered off, washed with water (5 x 30ml) to neutral pH and dried for 10 hours at 25°C and 0.3mm Hg over potassium hydroxide pellets to give N,N'-bis-acetyl 5-(N"-methyl acrylamido)-2,4,6-triiodoisophthaldiamide

(12) in nearly quantitative yield. TLC: (85% CHC1 ₃ /15% MeOH) Rf (11): 0.54; Rf (12): 0.70.

E. N,N'-bis-acetyl, N,N ^! -bis-allyl 5-(N"-methyl acryl- amido)-2,4,6-triiodoisophthaldiamide (13) N,N ^f -bis-acetyl ^' 5-(N"-methyl acrylamido)-2,4,6- triiodoisophthaldiamide (12) (2.13g, 3mMoles) was placed in a flask and distilled dimethyl sulfoxide (6ml) was added, with stirring. Potassium carbonate (1.04g, 7.5mMoles) was added to a homogenized solution followed by distilled allyl chloride (0.918g, 12mMoles) over a one minute period.

After 8 hours at 45°C, the product was isolated by pouring the mixture into a stirred slurry of ice:brine:l N HC1 (10g:20ml:10ml) . The precipitate was filtered off, washed with water (6 x 10ml) to neutral pH and dried overnight at ambient temperature and 0.4mm Hg over F ₂ ° ₅ * ^Tn i ^s gave N,N'-bis-acetyl, N,N'-bis-allyl 5-(N"-methyl acrylamido)-2,4,6,-triiodoisophthaldiamide

(13) (2.05g, 87% yield). TLC: (90% CHC1 ₃ :10% MeOH, Rf: 0.87).

F. N,N'-bis-allyl 5-(N"-methyl acrylamido)-2,4,6-tri- iodoisophthaldiamide (5)

A solution of 0.8g N,N'-bis-acetyl, N,N'-bis- allyl, 5-(N"-methyl acrylamido)-2,4,6-triiodois phthaldi- amide (13) (l.OlmMoles) in 5ml dioxane and 5ml 0.5N sodium hydroxide was heated at 40°C for 2 hours in an oil bath.

The product was isolated by pouring the reac¬ tion mixture into an ice-brine slurry (1:1, 20ml), fol- lowed by filtration. The solid was washed with water (6 x 5ml) and dried at 4mm Hg and 62°C for 60 hours to give N,N'-bis-allyl 5-(N"-methyl acrylamido)-2,4,6-tri- ' iodoisophthaldiamide (5) (655mg, 92% yield).

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This product is the same as in Examples IB (5) and IC (5).

EXAMPLE IIA

A. N,N'-bis-acetyl 5-diacetylamino-2,4,6-triiodoisoph- thaldiamide (14)

To a cooled, stirred suspension of 5-amino- 2,4,6-triiodoisophthaldiamide (9) (20g, 0.036mole) in acetic anhydride (120ml), cone. H ₂ S0 ₄ (7ml) was added over 20 in. After 6 hours at 50°C the reaction mixture was poured into ice cold water (900ml), filtered, washed with water (500ml), 10% bicarbonate solution, and water, triturated with toluene, the solvent removed, and the solid dried under vacuum at 44°C. The product contained 85% of N,N ^! -bis-acetyl 5-diacetylamino-2,4,6-triiodo- isophthaldiamide (14). The product was employed in the next step without purification.

B. N,N'-bis-allyl 5-(N"-allyl N"-acetyl amino)-2,4,6- triiodoisophthaldiamide (15)

To a stirred solution of crude (14) (2.69g, 3.72mMole) in DMA (13ml), powdered potassium hydroxide (0.937g, 16.73mMole) was added and the contents stirred at 40°C for 4 hours.

Sodium bicarbonate (0.336g, 4mMole), potassium carbonate (0.75y, 5.56mMole) and allyl chloride (1.8ml, 22.2mMole) were added under stirring at 40°C for 6 hours. The acetimides were hydrolyzed off in situ with IN sodium hydroxide (9.5ml) and water (5ml) at 50°C in 1.5 hr. ■ The reaction mixture from which the product had partly precipitated out was poured into ice cold water, the solid filtered, washed and dried (yield 1.82g, ca70% isolated yield; 90% yield by TLC). N,N ^« -bis-allyl 5- (N"-allyl, N"-acetyl amino)-2,4,6-triiodoisophthaldiamide (15) was crystallized from acetone-hexane as colorless needles.

C. N,N'-bis-(2',3'-dihydroxypropyl) 5-(N"-2"^"-di¬ hydroxypropyl, N"-acetyl amino)-2,4,6-triiodoisophthal- diamide (16) (Iohexol)

To a cooled, stirred suspension of (15) (2g, 2.78mMole) in acetone (10ml) were added aqueous tetra- ethylammonium acetate (0.125g, 0.55mMole), 70% aqueous t.-butyl hydrogen peroxide (1.6ml, 12.5mMole), and aqueous osmium tetroxide (0.007g, 0.028mMole). The reaction mixture was kept in an oil bath for 3 hours at 45-48°C and then at room temperature for 6 hours. Excess peroxide was removed from the reaction mixture with 10% ^• aqueous sodium sulphite solution (10ml); after adjusting the pH to 6.5 with diluted HC1, the solution was evapo¬ rated to dryness in vacuo. The product was dissolved in water (30ml), adsorbed on Diaion resin and eluted with water, then with a water-methanol mixture. From water and methanol-water (10%) eluents, N,N'-bis-(2' ,3'-dihy¬ droxypropyl) 5-(N ^u -2,3-dihydroxypropyl N"-acetyl amino)- 2,4,6-triiodoisophthaldiamide (16) was obtained (1.80g, 85% yield) as a white powder.

Comparison of (16) with Iohexol (Nyegaard Co.) showed it to be identical by HPLC (aminopropyl silica, 90 acetonitrile/10 H ₂ 0).

EXAMPLE IIB A. N,N'-bis-(2' ,3'-dihydroxypropyl) 5-(N"-2",3"-dihy¬ droxypropyl, N"-acetyl amino)-2,4,6-triiodoisophthal- diamide (16)

N,N'-bis-(2' ,3'-dihydroxypropyl) 5-acetylamino- 2,4,6-triiodoisophthalamide (17) prepared as described in U.S. Patent No. 4,250,113 (375mg, 0.5mMole) was heated at 85°C with sodium bicarbonate (84mg, l.OmMole) and epichlorohydrin (2ml, 26.6mMole) in 1,2-propanediol (4ml) and a trace of water for 60 min to give N,N'-bis- (2' ,3'-dihydroxypropyl) 5"-(N"-2",3"-dihydroxypropyl, N"-acetyl amino)-2,4,6-triiodoisophthaldiamide- (16)

(Example IIA) in 95% yield. TLC: CHC1 ₃ : MeOH 6:4, HPLC:

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90 acetonitrile:10 water, 2ml/min, NH ₂ propyl 0.5 x 25, lOμ Alltech column.

EXAMPLE IIIA

A. 3,5-diaminobenzamide bis-hydrochloride (19) 3,5-dinitrobenzamide (18) (412.0g, 2.00moles,

Aldrich) was added to a suspension of 10% Pd/C (10.4g) in concentrated HC1 (360ml) and water (3.64L). The mixture was hydrogenated at 60psi in a Parr hydrogenation apparatus until hydrogen was no longer being consumed. The solution was filtered through a Celite pack and washed with 500ml water. The filtrate and washings of 3,5-diaminobenzamide bis-hydrochloride (19), were com¬ bined and used for the subsequent iodination.

B. 3,5-diamino-2,4,6-triiodobenzamide (20) The 3,5-diaminobenzamide bis-hydrochloride

(19) was diluted with water to 20.0L, stirred and, over a twenty minute period, 3.2 equivalents of KIC1 ₂ (4.12L of 1.55M KIC1 ₂ ) were added.

After 15 minutes, the mixture was filtered, washed once with 1L water and twice with 1.5L of metha¬ nol at 50°C, and dried.

843.5g of the crude product was dissolved in 5.5L of DMA at 55°C, treated with decolorizing charcoal (20g) and filtered. 1.5L water was added until crystals began forming. The solution was cooled to 0°C overnight, and the crystalline product was filtered and washed with a 1:1 mixture of DMA and water (2 x 500ml), with water (2 x 400ml), _. and finally with acetone (300ml). The product was dried in vacuo to yield 3,5-diamino- 2,4,6-triiodobenzamide (20) (844.2g, 79.8% yield from (18)). TLC: single spot with an Rf of 0.46 on silica with 90 CHC1 ₃ /10 methanol.

C. N-acetyl 3,5-bis-diacetylamino-2,4,6-triiodobenz- amide (21) At room temperature, concentrated sulfuric acid (22.6ml, 1% by volume) was added over 0.5 hour

with vigorous stirring to a slurry of 3,5-diamino-2,4,6- ^* triiodobenzamide (20) (599.72g, 1.13moles) in acetic anhydride (2.26L), and the reaction was heated at 90°C for 10 hours. The reaction mixture was slowly poured into 4 times its volume of water. The precipitate was filtered, washed with 800ml cold water, and dried to yield N-acetyl 3,5-bis-diacetylamino-2,4,6-triiodobenzamide (21) (788.6g, 94.4% ^" yield). TLC: Rf of 0.63 on silica with 90 chloroform/10 ethanol. Greater than 98% pure with a retention time of 3.5 minutes. Column: Merck LiChrosorb CN (5u). Solvent system: 85 cyclohexane/9 te rahydro- furan/3 methanol/3 isobutanol. Flow rate: 2ml/min. NMR: singlet at 2.35ppm (15H), singlet at 9.00ppm (1H) in CDC1 ₃ . MP: 232-234°C (d). Elemental analysis: found:27.67%C, 2.25%H, 5.66%N, 51.27%I; expected:27.60%C, 2.17%H, 5.68%N, 51.66%I, 12.99%0. UV: λ _m __ = 240.Inm, ε = 31,156L/mole.cm. ^D _* N,N',N"-tris allyl 3,5-bis-acetylamino-2,4,6-tri- iodobenzamide (22)

To a solution of N-acetyl 3,5-bis-diacetyl- amino-2,4,6-triiodobenzamide (21) (184.75g, 250mMole) in DMA (500ml) at 0°C was added 60% sodium methoxide (60.7g) over a 2-hour period. A vacuum of 20mm Hg was applied for 1 hour. Allyl chloride (122ml, 1.5moles, distilled at 45-46°C) was added at 0°C over 30 minutes. The reaction mixture was stirred at room temperature for 8 hours. Fifty ml methanol and sodium methoxide (lg) were added, and the reaction mixture was stirred for an additional 10 minutes, then poured slowly into a stirred ice-cooled solution of 0.1N HC1 (2.5L). The resulting precipitate ^' was filtered,,, washed with water (5 x 400ml) and dried in vacuo to yield 169.6g).

Crystallization: 41.30g was dissolved in boil- ing diehloromethane (300ml), the solution was concen¬ trated to 150ml, hexane (60ml) was added until crystals began to form, and the solution was set aside at room

temperature for 24 hours. The crystals were filtered, washed with 1:1 dichloromethane-hexane (2 x 10ml) and dried to yield 32.9g. With a second crop (4.29g) the total yield was 90%. TLC: four iso ers with Rf's of 5 0.51, 0.55, 0.57 and 0.61 on silica in 90 chloroform/10 methanol. MP: mixture: 210°C. One isomer (Rf's on silica 0.51) has p 212-213°C; the other isomer (Rf 0.55) has mp 224.5-226°C. NMR: Doublet at 1.73ppm (6H), triplet at 3.9ppm (2H), doublet at 4.2ppm (4H), multi-

10 plet at 5.1ppm (6H), multiplet. at 5.8ppm (3H), broad singlet at 8.75ppm (1H) in DMSO-d6.

E. N' ,N"-tris(2 ' ,3'-dihydroxypropyl) 3,5-bis-acetyl- amino-2,4,6-triiodobenzamide (23)

(22) (38.44g, 52.44mMole) and potassium acetate

15 (1.03g, 1049mMole) were added to a solution of acetone

(50ml) and water (20ml), followed by addition of t.-butyl hydroperoxide (38.6ml of a 65% solution, 261mMole) and osmium tetroxide (1.329g, 5.24mMole). After 4 hours at room temperature, the reaction was poured into water

20 (50ml) and 0s0 ₄ and t.-butyl hydroperoxide extracted with ethyl acetate (5 x 75ml). 10% aqueous NaHC0 ₃ (6ml) was added to the aqueous phase, and the solution was desalted with BioRad AG5010X(*) D mixed bed resin (58cm x 3.5cm ID column, flow rate of 45ml/min of water).

25 The water was removed from the product to yield N,N' ,N"- tris-(2' ,3'-dihydroxypropyl) 3,5-bis-acetylamino-2,4,6- triiodobenzamide (23) (40.7g, 93% yield).

Analytical Data: HPLC: four isomers of (23) with retention times of ^" 14.5g, 19, 22 and 24 minutes •30 were resolved (Ratio: 23:46:26:5). They were isolated individually and slowly interconverted at room tempera¬ ture and somewhat faster in boiling water (25cm x 10mm ID Alltech aminopropyl column, lOμ 90:10 acetonitrile/wa- ter, lOml/min). NMR: singlet at 1.85ppm (6H)," multiplet 35 at 3.6ppm (15H), broad singlet at 4.5ppm (6H), triplet at 8.6ppm (1H), in DMSO-d6. Elemental analysis (mono- hydrate): found:28.17%C, 3.69%H, -4.79%N, 44.54%I. Ex-

pected: 28.13%C, 3.52%H, 4.92%N, 44.67%I. UV (mono- hydrate): = 245.2nm, ε = 31,180 1/mole in water.

EXAMPLE IIIB

A. N,N'-bis-allyl diatrizoic acid (25) Diatrizoate sodium (24) (635.8g containing

4.0% water per weight, 0.960mole, Sterling-Winthrop, Inc.) was dissolved in 660ml water containing 91.5g (2.4moles) sodium hydroxide. 204ml (2.5moles) of dis¬ tilled allyl chloride was added and the reaction mixture refluxed at 50-55°C for 3.5 hours, then cooled to room temperature and extracted with dichloromethane (5 x 200ml). The aqueous layer was heated to 45°C, stirred and 400ml of 3N HC1 was added. The solid product was cooled to 20°C, filtered and washed with ice-cold water (3 x 250ml). The material was dried in vacuo at 90°C. Yield of (24) 632.6g, 95.0%.

B. N,N'-bis-allyl diatrizoic acid chloride (26)

Purified thionyl chloride (380ml) was added to N,N'-bis-allyl diatrizoic acid (25) (261.2g, 376.4mMole) and the suspension heated under reflux with stirring for 1.3 hours. The solution was cooled to room temperature, and the thionyl chloride was distilled off under vacuum at 20-25°C and any traces removed by drying in vacuo over KOH to obtain an off-white amorphous powder (261.42g, yield 97.5%). MP: 232-234°C (dec). ^c - N,N' ,N"-tris-allyl 3,5-bis-acetylamino-2,4,6-tri- iodobenzamide (22)

N,N'-bis-allyl diatrizoic acid chloride (26) (1.50g, 2.11mMoles) was suspended in dichloromethane (10ml), and distilled allylamine (552μl, 7mMole) added slowly at 40°C with stirring for 40 min. The reaction mixture was washed with water (1 x 10ml), 0.1N HC1 (2 x 10ml), water (1 x 10ml) and then dried (MgS0 ₄ ). Solvent removal gave an off-white residue (1.55g) which was crystallized from dichloromethane-hexaήe (1.3g), yield 84%. MP: 207-208°C (dec).

D. N,N'-N"-tris(2' ,3'-dihydroxypropyl) 3,5-bis-acetyl- amino-2,4,6-triiodobenzamide (23)

A suspension of N,N' ,N"-tris-allyl 3,5-bis- acetylamino-2,4,6-triiodobenzamide (22) (3.2g, 4.37mMoles), potassium acetate (0.086g, 0.87mMoles), t.-butyl hydroperoxide (2.58ml of a 65% solution in water, 17.48mMoles), osmium tetroxide (O.llig, 0.437mMoles), acetone (27ml) and water (5ml) was stirred at room temperature for 6 hours. The reaction mixture was diluted with 50ml water and extracted with ethyl acetate (50ml x 3).

The aqueous layer was desalted on a BioRad AG-501 mixed bed column, and the water evaporated to give N,N' ,N"-tris-(2' ,3'-dihydroxypropyl) 3,5-bis-ace- tylamino-2,4,6-triiodobenzamide (22), (yield: 95%). (Identical to compound (22) from Example IIIA).

EXAMPLE IIIC A. 3,5-bis-diacetylamino-2,4,6-triiodobenzoic acetic mixed anhydride (28) A mixture of diatrizoic acid (27) (154g,

0.25mole), acetic anhydride (500ml, 0.5mole) and con¬ centrated sulfuric acid (10ml) was heated in an oil bath at 85°C, with stirring, for 4 hours. The reaction mixture was cooled, then slowly added, with Stirling, to water (1.5L) containing ice (500g). The precipitate was collected by suction- filtration, washed with water (7 x 100ml) and dried in vacuo at 50°C overnight to obtain the product, 3,5-bis-diacetylamino-2,4,6-triiodo- benzoic acetic mixed anhydride (28), as a white solid, 172g, yield 93%. TLC: Rf 0.5 (CHCl ₃ /MeOH/ACOH:75/20/5) . IR: (KBr) :1766cm ^"1 and 1797cm ^"1 (anhydride carbonyls), 1710 ^"1 (acetyl carbonyls). MP: 196 (dec). ^B * 3,5-bis-diacetylamino-2,4,6-triiodobenzoyl chloride (29) A suspension of the anhydride (28) (171g, 0.24mole) in thionyl chloride (300ml) was refluxed with

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mechanical stirring in an oil bath at 80°C for 1.5 hours. The excess thionyl chloride was removed in vacuo (20mm of Hg), and the residue coevaporated with ethyl acetate (4 x 60ml), and dried in vacuo overnight to obtain 3,5- bis-diacetylamino-2,4,6-triiodobenzoyl chloride (29)

(170g, quantitative yield). TLC: Rf 0.5 (carbon tetra- chloride/acetone: 8/2). MP: 231-232°C. IR: (KBr): 1763cm ^" (acid chloride carbonyl), 1710cm ^" (acetyl carbonyls) . C. N-(2' ,3'-dihydroxypropyl) 3,5-bis-acetylamino- 2,4,6-triiodobenzamide (30)

2,3-Dihydroxypropylamine (12.10g, 0.0133mole) in DMA (10ml) was added to an ice-cold solution of 3,5- bis-diacetylamino-2,4,6-triiodobenzoyl chloride (29) (35.83g, 0.05mole) in DMA (50ml), with stirring, for 10 min. The reaction mixture was stirred at room tempera¬ ture, and let stir for 5 hours. Concentrated ammonium hydroxide (30ml) was added. After 30 min, all solvents were removed in vacuo at 60°C. To the residue, IN hydrochloric acid (50ml) was added and the solvent removed in vacuo. The residue was mixed with ice cold water (150ml) and the precipitate was filtered, washed with water and dried to obtain the product, N-(2',3'- dihydroxypropyl) 2,5-bis-acetylamino-2,4,6-triiodobεnz- amide (30), as a white solid in high yield. TLC: (silica gel): 0.36 in CHCl ₃ /MeOH 8:2. NMR: (DMSO-dg): COCH ₃ (2.02, singlet, 6H); (-CH ₂ - and -CH protons (3.05 to 3.85, broad ultiplet, 5H); -OH (4.2, singlet); ArCOHN- (8.4 to 8.7, broad triplet, 1H); Ar-NHCO- (9.85 to 10.15, broad doublet, 2H) .

D. N,N'-N"-tris-(2' ,3'-dihydroxypropyl) 2,4,6-triiodo- benzamide (22)

N-(2' ,3'-dihydroxypropyl) 3,5-bis-acetylamino-

2,4,6-triiodobenzamide (30) (136mg, 0.2mMole) was heated with sodium bicarbonate (336mg, 4mMole) and epichloro- hydrin (1ml, 13.3mMole) in 1,2-propanediol (2ml) and a trace of water at 85°C for 1 hour, to give N,N'-N"-

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V >

tris-(2' ,3'-dihydroxypropyl) 3,5-bis-acetylamino-2,4,6- triiodobenzamide (Example IIIB (23)) in 96% yield by HPLC. HPLC: acetonitrile:water 90:10, 2ml/m, NH ₂ propyl, 0.5 x 25cm, lOμ Alltech column.

EXAMPLE HID

A. N-(2',3 '-dihydroxypropyl) 3,5-bis-(N'-allyl N'- acetyl amino)-2,4,6-triiodobenzamide (31)

N,N'-bis-allyl-diatrizoic acid chloride (26) (see Example IIIA for preparation) (142.6g, 200mMole) was suspended in dry DMA (200ml). 3-Amino-l,2-pro ane- diol (35ml, 2.25eq.) was added over 20 minutes with stirring and cooling to keep the temperature of the reaction mixture at 60°C, then stirred at 60°C for an additional 30 minutes. TLC -(90 HCC1 ₃ /10 MeOH) indicated 90% conversion to a single product, Rf 0.3. The mixture was poured slowly into stirred ice-water (2L); the re¬ sulting solid was filtered, washed twice with 100ml ice-cold water and dried in vacuo at 60°C. MP: 220- 221°C (dec). B. N,N' ,N"-tris-(2' ,3'-dihydroxypropyl) 3,5-bis-acetyl- amino-2,4,6-triiodobenzamide (23)

Osmium tetroxide (12ul of a 0.79M solution, 0.95μMole) and t.-butyl hydroperoxide (73μl of a 65% ^• -solution, 47μMole) were added to a suspension of N- (2' ,3'-dihydroxypropyl) 3,5-bis-(N'-allyl N'-acetyl amino)-2,4,6-triiodobenzamide (31) (72.4mg, 9.4μMole), potassium acetate (5.0mg) in acetone (900μl), and water (50μl) and the reaction allowed to proceed at room tem¬ perature for 4 hours to yield N,N' ,N"-tris-(2' ,3'-di- hydroxypropyl) 3,5-bis-acetylamino-2,4,6-triiodobenzamide (23), identical to product (23) from Example IIIA (yield

X ; )i •

EXAMPLE IV A. N-(1' ,3'-dihydroxyprop-2-yl) 3,5-bis-(N ^f -allyl, N'-acetyl amino)-2,4,6-triiodobenzamide (32)

N,N'-bis-allyl diatrizoic acid chloride (26) (see Example IIIB) (35.6g, 50mMole) was suspended in a stirred, dry DMA solution (63ml). To this solution was added 2-amino-l,3-propanediol, 4.1M in DMA (37ml, 3.0 eq. ) over a 10 minute period and the reaction mixture stirred for 1.5 hours. The mixture was poured slowly into stirred, ice-cooled water (1:1), the resulting solid was filtered, washed twice with 50ml of ice-cooled water, and dried in vacuo. TLC: Two isomers with Rf's of 0.33 and 0.37 in chloroform 9:methanol 1. TLC indi¬ cated quantitative conversion to (32). MP: 240-243°C (dec). UV: k _^v ^~~ 245.2nm, ε = 33,950 1/mole cm. NMR: (DMSO-d6) 1.85-1.60 (d, 6H), 3.9-3.4" (M, 5H), 4.25-4.05 (d, 4H), 6.1-5.4 (M, 2H), 8.6-8.4 (d, 1H). Elemental analysis: Calculated: 31.31%C, 3.15%H, 5.48%N, 49.63%I; Found: 30.99%C ₇ 3.31%H, 5.32%N, 49.00%I. B. N-(l' ,3'-dihydroxyprop-2-yl) ^• 3,5-bis-(N ^f -acetyl,

N'-(2",3"-dihydroxypropyl) ^• amino)-2,4,6-triiodobenzamide

1331

A suspension of N-(l,3-dihydroxyprop-2-yl) 3,5-bis-(N'-allyl, N'-acetyl amino)-2,4,6-triiodobenz- amide (32) (3.83g, 5.0mMole), potassium acetate (0.99g, l.OmMole) t.-butyl hydroperoxide (3ml of a 65% solution in water, 20.4mMole), osmium tetroxide (0.635ml of a 0.787M solution in acetone, 0.5mMole), acetone (8ml) and water (2ml) was stirred at room temperature for 5 hours. The mixture was then- diluted with 10ml of water and washed with ethyl acetate (6 x 10ml) .

The aqueous solution was passed through a BioRad AG-501-X8(D) mixed bed column, and the water evaporated. Drying under vacuum (1.0mm Hg) at room temperature for 1 hour gave the product N-(l',3'-di- hydroxyprop-2-yl) 3,5-bis-(N'-acetyl, N'-(2"^"-dihy¬ droxypropyl) amino)-2,4,6-triiodobenzamide (33) (in

quantitative yield). Elemental analysis: Calculated: 28.76%C, 3.38%H, 5.03%N, 45.59%I; Found: 28.43%C, 3.40%H, 4.91%N, 44.21%I. NMR: (DMSO-d6) 8.64-8.2 (m, 1H), 4.8- 4.35 (m, 6H) disappears after' addition of CF ₃ C0 ₂ D, 4.1- 3.0 (m, 15H), 1.9-1.6 (d, 6H) . UV: λ _ _v = 245.4nm, ε = 31,900 1/mole.cm. TLC: Two isomers with Rf's of 0.47 and 0.56 in n-butanol 6.5N acetic acid 4.

EXAMPLE V

A. N,N'-bis-(3 _/ 5-bis-(N"-allyl, ^" N"-acetyl amino)- 2,4,6-triiodobenzoyl) ethylenediamine (34)

To a stirred suspension of N,N'-bis-allyl- diatrizoic acid chloride (26) (see Example IIIB) (5.11g, 7.0mMole) in DMA (70ml), distilled ethylenediamine (0.5ml, 15mMole) was added at room temperature. After 8 hours it was filtered through Celite. Solvents were distilled off and the residue dissolved in a mixture of THF (150ml) and ethyl acetate (50ml). The solution was washed with a mixture of brine and IN HC1 (1:1) (1 x 50ml), water (2 x 50ml), and with brine (1 x 50ml). The organic layer was dried (MgS0 ₄ ). Filtration, fol¬ lowed by removal of the solvent, yielded the product as an off-white solid (3.29, yield 66.6%).

B. N,N'-bis-(3,5-bis-(N"-(2' ,3'-dihydroxypropyl) , N"- acetyl amino)-2,4,6-triiodobenzoyl) ethylenediamine (35) Osmium tetroxide (54mg, .21mMole) was added to a suspension of N,N'-bis-(3,5-bis-(N"-allyl, N"-acetyl amino)-2,4,6-triiodθbenzoyl) ethylene diamine (34) (3.325g, 2.15mMole) in a mixture of water (5ml), acetone (19ml) and dioxane (40ml) containing potassium acetate (45mg, 0.46mMole) and t.-butyl hydroperoxide (2.50ml of a 65% aqueous solution, 17mMole). The mixture was stirred at 25-30°C for 17 hours. Acetone and dioxane were evapo¬ rated, water (50ml) was added and the mixture filtered and extracted into ethyl acetate. 10% Aqueous NaHS0 ₃ (2.5ml) was added to the aqueous phase, the salts were, removed on a mixed bed resin (BioRad AG-501-X8-(D)),

and the solution was concentrated to yield the product (35) in nearly quantitative yield by TLC, which was puri¬ fied. TLC: Four isomers with Rf's of 0.44, 0.49, 0.52 and 0.55 on silica gel in 9:1 chloroform:methanol.

EXAMPLE VIA

• A. N-(2,3-dihydroxypropyl) ethylenediamine (36)

Following the procedure of Surrey et al., J. Am. Chem. Soc (1952) 74:4102, 3-chloro-l,2-propane- diol (8.36ml, O.lOmole) was added dropwise over 15 min to stirring ethylenediamine (66.8ml, l.Omole) at room temperature. After the addition was complete, the solu¬ tion was heated at approx. 60°C until the 3-chloro-l,2- propanediol was consumed (about 1 hour), as determined by TLC. NaOH (4.4g, O.llmole) was added to the solution and excess ethylenediamine was vacuum distilled off fol¬ lowed by careful fractional distillation to yield 5.76g (43%) of (36) (b.p. 162°C/2.0mm).

B. N-(2' ,3 '-dihydroxypropyl) , N,N'-bis-(3,5-bis- acetylamino-2,4,6-triiodobenzoyl) ethylenediamine (37) Into a cooled (0-5°C) stirred solution of

3,5-bis-diacetylamino-2,4,6-triiodobenzoyl chloride [(29) see Example IIIC] (100.Og, 0.153mole) -and tri- ethylamine (43ml, 0.306mole) in DMA (450ml), was added dropwise a solution of N-(2,3-dihydroxypropyl) ethylene- diamine (36) (12.33g, 0.92mole) in DMA (60ml) over a 30 minute period. The reaction mixture was stirred for 18 hours at room temperature, and then poured into 2.5L of 0.1N HCl. The precipitate.was filtered, washed with water tb neutral pH, and vacuum-oven dried, and dis- solved in methanol (350ml) containing sodium methoxide (2.26g, 0.042mole), and refluxed for 1.5 hours. The methanol was distilled off, the solid dissolved in water (200ml), and precipitated with l.ON HCl, filtered, washed with water (2 x 100ml) and vacuum oven dried to yield (37) 22.5g. TLC: Chloroform 15:methanol4:acetic acid 1. One spot with ^" an Rf of 0.30. TLC indicated 95%

conversion NMR: (d6-DMSO) 2.0 (S, 12H), 4.3-2.8 (M, 11H) goes to 9H after addition of CF ₃ C0 ₂ H, 4.9-4.3 (M, 2H) disappears after addition of CF ₃ C0 ₂ H, 9.0-8.4 (br S, 1H), 10.3-9.8 (br S, 4H). C. N-(2' ,3'-dihydroxypropyl), N,N'-bis-(3,5-bis(N"- allyl, N"-acetyl amino)-2,4,6-triiodobenzoyl) ethylene¬ diamine (38)

A stirred solution of N-(2 ' ,3 '-dihydroxypropyl) N,N'-bis-(3,5-bis-(N"-allyl, N"-acetyl amino)-2,4,6-tri- iodobenzoyl) ethylenediamine (37) (25.Og, 0.019mole), allyl chloride (12.32ml, 0.15mole), water (33ml), metha¬ nol (155ml) and potassium carbonate (26.1g, 5.3mole) was heated to 43°C for 24 hrs. All solvents were evap¬ orated off and the residue redissolved into 200ml of DMA, and poured into stirred water (600ml). A precipi¬ tate was washed with water (2 x 100ml) and vacuum oven dried to yield (38) 15.8g (56.6%). TLC: Chloroform 9:methanol 1. Four isomers with Rf's of 0.39, 0.40, 0.43 and 0.45. NMR: (DMSO-d6) 1.75 (S, 12H), 4.5-2.7 (M, 19H), 5.4-4.8 (M, 8H), 6.2-5.4 (M, 4H), 8.3 (S, 1H) . TLC: The product appears as four isomers with Rf's of 0.39, 0.40, 0.43 and 0.45 in chloroform 9:methanol 1.

EXAMPLE VIB A. N-(2' ,3'-dihydroxypropyl) , N,N'-bis-(3,5-bis-(N"- allyl, N"-acetyl amino)-2,4,6-triiodobenzoyl) ethylene¬ diamine (38)

N,N'-bis-allyl diatrizoic acid chloride (26) (42.12g, 0.059raole) and triethylamme (16.4ml, O.llδmole) was suspended in an ice-cooled, stirred, dry DMA solu- tion (200ml). To this was added dropwise a solution of N-(2,3-dihydroxypropyl) ethylenediamine (36) (4.76g, 0.35mole) in DMA (95ml) over 15 minutes, and the mixture stirred at room temperature for 48 hours. The mixture was poured slowly into 1L of stirred water to yield a solid product (38). TLC indicated over 95% conversion.

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B. N-(2'3'-dihydroxypropyl), N-,N'-bis-(N",N"-bis- (2",3"-dihydroxypropyl) 3,5-bis-acetylamino-2,4,6-tri- iodobenzoyl) ethylenediamine (39)

Into a solution of water (6.34ml), acetone (25.35ml), potassium acetate (49.87mg, 0.50mMole), t.- butyl hydroperoxide (7.51ml of a 65% solution in t.- b ^' utanol, 50.8mMole) and osmium tetroxide (3.21ml of a Ig 0s0 ₄ in 50ml t.-butanol solution, 0.25mMole) at room temperature, was added to N-(2' ,3'-dihydroxypropyl) N,N'-bis-(3,5-bis-(N"-allyl, N"-acetyl amino)-2,4,6- triiodobenzoyl) ethylenediamine (38) (9.43g, 6.34mMole). After stirring for 22 hours at room temperature, 63ml of water was added to the reaction mixture, which was ex¬ tracted with ethyl acetate (3 x 60ml). The aqueous layer was evaporated, redissolved in water and desalted by a mixed bed ion exchange resin (AG-501-X8(D) )- The solu¬ tion was evaporated to yield 8.4g (81.6%) of N-(2',3'- dihydroxypropyl). N, '-bis-(N", "-bis-(2",3"-dihydro- hydroxypropyl) 3,5-bis-acetylamino-2,4,6-triiodobenzoyl) ethylenediamine (39). NMR: (d6-DMSO) 1.8 (S, 12H),

4.2-2.7 (M, 29H), 5.1-4.2 (br S, 12H) disappears upon addition of CF_,C0-,H, 9.1-8.4 (br S, 1H) . UV: λ _m=v = 246.Onm, ε = 67,280 1/mole.cm.

EXAMPLE VII A. N-(2'-hydroxyethyl), N,N'-bis-(3,5-bis-acetyla ino- 2;4,6-triiodobenzoyl) ethylenediamine (40)

Into a cooled (0-5°C), stirred solution of 3,5-bis-diacetylamino-2,4,6-triiodobenzoyl chloride (29), (50.0g, 0.077mole) and triethylamme (21.4ml, 0.154mole) in DMA (182ml), was added dropwise a solution of N-(2-hydroxyethyl ethylenediamine (4.66ml, .046mole) in DMA (10ml) over a 30-minute period. The reaction mixture was stirred at room temperature for 18 hours, then poured into 1.0L of 0.1N HCl. The precipitate was filtered, washed with water to neutral pH, and vacuum " oven dried. The residue was dissolved in methanol

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(273ml) containing sodium methoxide (6.51g, 0.12mole) and refluxed for 1.5 hours. The methanol was distilled off, the solid dissolved in water (150ml), and precipi¬ tated with l.ON HCl, filtered, washed with water (2 x 100ml) and vacuum oven dried to yield 34.08g (96.3%,

0.26mole) of N-(2'-hydroxyethyl), N,N'-bis-(3,5-bis-ace- tylamino-2,4,6-triiodobenzoyl) ethylene diamine (40). TLC: Chloroform 15:methanol 4:acetic acid 1. Product Rf: 0.39. NMR: (DMSO) 9.95 (br S, 4H), 9.0-8.5 (br S, IH), 4.0-2.9 (br M, 15H) goes to 8H after addition of ^• CF ₃ C0 ₂ H, 2.05 (S, 12H).

B. N-(2'-hydroxyethyl) , N,N'-bis-(3,5-bis-(N"-allyl, N" acetyl amino)-2,4,6-triiodobenzoyl) ethylenediamine iϋl A stirred solution of N-(2'-hydroxyethyl)

N,N'-bis-(3,5-bis-acetylamino-2,4,6-triiodobenzoyl) ethylenediamine (40) (15.0g, 0.012mole), allyl chloride (10.68ml, 0.13mole), water (17ml), methanol (83ml) and potassium carbonate (12.46g, 0.09mole) was heated at 43°C for 24 hrs. All solvents were distilled off, the remaining solid filtered, washed with water and vacuum oven dried to yield 12.95g (76.9% isolated yield) of N-(2'-hydroxyethyl), N,N'-bis-(3,5-bis-(N"-allyl, N"- acetyl amino)-2,4,6-triiodobenzoyl) ethylenediamine (41). TLC: Chloroform 9:methanol 1. TLJ indicated substantial¬ ly quantitative yield. The product gives four isomers with Rf's of 0.52, 0.56, 0.60 and 0.65. NMR: (DMS0-d6) 1.75 (S, ^' l2H), 4.5-2.7 (M, 40H) goes to 16H after addi¬ tion of CF_C0,H, 5.4-4.8 (M, 8H), 5.4-4.7 (M, 8H), 6.2- 5.45 (M, 4H), 9.1-8.4 (br M, IH) .

C. N-(2'-hydroxyethyl) N,N'-bis-(3,5-bis-(N"-2",3"- dihydroxypropyl, N"-acetyl amino)-2,4,6-triiodobenzoyl) ethylenediamine (42)

A suspension of N-(2'-hydroxyethyl), N,N'-bis- (3,5-bis-(N"-allyl, N"-acetyl amino)-2,4,6-triiodobenz- • oyl) ethylenediamine (41) (12.0g, 8.24mMole), potassium acetate (0.065g, 0.66mMole), t-butyl hydroperoxide

(9.72ml of a 65% solution in water, 65.9mMole), osmium tetroxide (4.19ml of a 0.0787M solution in t-butanol, 0.33mMole), acetone (33ml) and water (8.2ml) was stirred at room temperature for 26 hrs, was diluted with 80ml of water, and washed with ethyl acetate (3 x 76ml). The resulting aqueous solution was passed through a BioRad AG-501-X8(D) mixed bed column, and the water evaporated. The residue was dried under vacuum (1.0mm Hg, RT) for 1 hr, yielding 11.08g (6.96mMole, 84.5%) of crude N-(2'-hydroxyethyl), N,N'-bis-(3,5-bis- (N-2",3"-dihydroxypropyl, N"-acetyl amino)-2,4,6-tri- iodobenzoyl) ethylenediamine (42). NMR: (DMS0-d6) 1.75 (S, 12H), 5.0-2.7 (M, 39H) goes to 28H with the addition of CF ₃ C0 ₂ H, 9.1-8.6 (br S, IH) . The above procedures describe novel efficient and flexible synthetic strategies which allow for the production of inexpensive non-ionic contrast media in high yield and purity. The method provides for selec¬ tive substitution of nitrogens depending upon whether they are benzamide nitrogens or aniline nitrogens, where peracylation can be achieved with inexpensive reagents and acyl groups removed selectively to allow for selective nitrogen substitution.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.