DESC:FIELD OF INVENTION
The present invention generally relates to chemical process. In particular it pertains to a novel and commercially viable process for preparation of Iohexol and its intermediates.

BACKGROUND OF THE INVENTION
Iohexol (1) is the non-proprietary name of the chemical drug substance of a non-ionic iodinated X-ray contrast agent marketed under the trade name OMNIPAQUE which is one of the most used agents in diagnostic X-ray procedure. Iohexol, [5-[N-(2,3-dihydroxypropyl)acetamido]-N,N'-bis(2,3-dihydroxy propyl)-2,4,6-triiodoisophtalamide is used in diagnostics as X-ray non-ionic contrast agent. It has been described for the first time in the British pat. 1,321,591. Its synthesis is well documented in German Pat. 2,547,789 and U.S 4,001,323. Iohexol (1) is water-soluble, has maximum general and neurotropic tolerance, a relatively high viscosity and maximum stability towards hydrolytic effects. For its use in diagnostics, Iohexol is administered at high doses and therefore they must have extremely high requirements of purity. Another inherent problem of the molecule is that the material is very hygroscopic and needs to be handled with care.

Several methods have been disclosed in the literature for the synthesis of Iohexol. The use of 2-methoxyethanol and mixtures of 2-methoxyethanol/isopropanol and a solvent chosen from a C1-C5-monoalkylether of a C3-C10 alkylene-glycol are respectively disclosed in WO 98/08804 and WO 2005/003080 as reaction solvents in which the N-alkylation of the nitrogen atom of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is carried out.

Several methods which can be used to produce high purity bulk pharmaceutical products. Possibly the most efficient method for the production of high purity product is a chromatographic process. However, in the present instance such a method is difficult to implement given the extremely large quantities of product that are necessary. Nevertheless, the chemical methods, such as crystallization or precipitations are the most suitable but they do not always allow the successful removal of impurities with molecular structures that are very similar to that of the preliminary product. In the case of Iohexol, the most problematic impurities are O-alkylated derivatives. In terms of the molecular configuration in the crystal, the properties of these substances are very similar to those of Iohexol being easily introduced in the crystalline structure which inevitably demands a lot of purifications and passing through the high concentrated resins.

The prior art cites various solvent systems considered adequate for the crystallization of Iohexol. The first of these systems comprises the use of butanol as described in US Pat. 4,250,113. In this case, the so-obtained product required subsequent dissolution in water, followed by evaporation to dryness under vacuum, in order to remove the residual butanol from the crystallized product. US Pat. 5,191,119 describe the purification of Iohexol using a chromatographic procedure. The product is obtained from a 10% methanol/water eluent mixture by an undisclosed process. Spanish Pat. 532,390 describe the crystallization of Iohexol using a mixture of aqueous methanol/isopropanol.

US Pat. 5,204,086 states that the most effective method of purification of Iohexol is crystallization from boiling isopropanol, but it was found that only 25-30% of the O-alkylated products could be removed in a single crystallization. Also further crystallizations significantly increase the cost of the process. In addition to the insufficient removal of the O-alkylated products, the inventors of the present invention have verified that the product of this last process contains approximately 1000 ppm of isopropanol. The drying step, even though prolonged, does not allow to reduce the isopropanol content to below several hundred parts per million. It is to be noted that the Iohexol monograph published in the 3rd Edition of the European Pharmacopoeia limits the presence of isopropanol to 100 ppm. The same monograph limits methanol and 2-methoxy ethanol contents to 50 and l00 ppm, respectively. The United States Pharmacopeia limits the content of the O-alkylated products to 0.6%.
In order to overcome the problem of high residual solvent content, the procedure which is currently following is to dissolve the Iohexol in water, followed by freeze-drying or spray-drying, by which the product is obtained as an amorphous solid. An obvious disadvantage of this procedure is the requirement of removal of O-alkylated impurities to carry out purification processes followed by the use of extremely expensive equipment and process.
According to procedures defined in the prior art, after completion of the reaction, crude Iohexol is isolated by removal of the high boiling solvent such as 2-methoxyethanol, usually by distillation, followed by purifying the crude product by known methods and finally, crystallizing from a suitable alcohol as described in U.S. Pat. 6,469,208 and references cited therein, or from mixtures of solvents including the high boiling reaction solvents and alcohols such as methanol as disclosed in WO2005/003080 or 1-methoxy-2-propanol either alone or mixed with other solvents such as isopropanol as claimed in U.S. Pat. 6,897,339.
Another problem of existing methods is that in the final reaction step, the conversion of 5-acetamino-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodobenzenedicarboxamide to Iohexol, large quantities of sodium chloride can be produced. The removal of this salt thus requires ion-exchange resins resulting in increased cost and loss of product.

US Pat. 5,705,692 and WO98/13334 describes the N-acetylation step where used dimethyl acetamide and acetyl chloride in 24 hrs at RT whereas the present invention reveals the best condition for preparing N-Acetyl compound (7) is to using of N-Methyl Pyrrolidine and DMF at 40°C to 45°C in 6 to 8 hrs time with a very high yield and purity.

However, prior art procedures are not always amenable to large scale production as they may require inconvenient separation steps or the use of difficult to handle reagents and/or result in relatively low yields. For instance, Haavaldsen et al (Acta Pharm. Suec. 20: 219-232 (1983)) proposed a multi-step procedure which isolates an intermediate by filtration from acetic anhydride/sulfuric acid. In addition, the yield from the first step is reported to be only 65%.

Moreover, most of the patents describes the synthesis of Iohexol from so called intermediate of 5-amino-2,4,6-triiodo isophthalic acid (AITPA). The preparation of AITPA itself is a difficult task as observed practically in commercial batches of this present invention. Iodination never completes with desired product but always end up with mono and di impurities in a substantial amount. The Iodination technique as described in the U.S. Pat. 4,001,323, U.S Pat. 2,820,814 and WO/2013/063737 shown deviation in either yield wise or ended up low purity where in the essential presence of mono and di iodo impurities of ATIPA. In order to obtain best purities in Iopamidol its needs to be purified every stage starting from isophthalic acid nitration through triiodination till Iohexol. US Patent Number 5,204,086 describes the synthesis of Iohexol where in the reaction proceeds one pot with AITPA-Cl and aminodiol and chlorodiol without isolation. This process apparently fails in explain to get desired purity of 99% and how to remove O-alkylated impurities.

Another problem of existing methods is that in the final reaction step, the conversion of 5-acetamino-N,N'-bis-(2,3-dihydroxypropyl)-2,4,6-triiodobenzenedicarboxamide to Iohexol, large quantities of sodium chloride can be produced. The removal of this salt thus requires ion-exchange resins resulting in increased cost and loss of product.

It is worth understanding that the product obtained by the process which discloses in the above mentioned patents essentially involves either usage of strong resins and other available chromatographic techniques including preparative chromatography to eliminate the amounts of by-products and impurities.

The final step in the synthesis of Iohexol is a N-alkylation step in which 5-(acetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6 triiodoisophtalamide (hereinafter Diamide (9)) is reacted in the liquid phase with an alkylating agent to introduce the 2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido group.

The manufacture of Iohexol is disclosed for example in US Pat. 4,250,113 . In the last step of the multistep chemical synthesis crude Iohexol is obtained from the reaction between Diamide and 3-chloro-1, 2,-propandiol at ambient temperature in propylene glycol and in the presence of sodium methoxide. The solvent is then evaporated and crude Iohexol is obtained. The crude product is evaporated to dryness and recrystallised twice from butanol.

Several suggestions to improve the N-alkylation and the purification steps have been published. WO 98/08804 discloses the use of 2-methoxy-ethanol and optionally isopropanol both in the alkylation step of Diamide and in the purification of crude Iohexol. WO 02/083623 discloses the purification of crude Iohexol using 1-methoxy-2-propanol as the solvent optionally in a mixture with other solvents. The N-alkylation step where Diamide (9) in solution is reacted with an alkylation agent such as 3-chloro-1, 2 -propandiol to introduce the 2,3-dihydroxypropyl group at the nitrogen of the 5-acetamido group is illustrated in Scheme-1:

Apparently, the N-alkylation step is challenging because O-alkylated by-products can also be formed when the alkylation occurs at the oxygen atoms of the hydroxyl groups. It is therefore a desire to limit the formation of these O-alkylated by-products and thereby to limit their presence in the final purified Iohexol. The upper limit for values for O-alkylated by-products in the end product is fixed by the European Pharmacopea to 0.6% (HPLC by area).

The O-alkylated by-products are removed to the degree desired or necessary by recrystallisation steps. Further unidentified by-products also referred to as impurities are also formed during the alkylation reaction and must be reduced to a tolerable level. In addition the solvents used should be easily available, be environmentally friendly and be of low toxicity.

There is, therefore a necessity to identify solvents which can be used in the N-alkylation reaction. It is further desired to improve the overall process including the N-alkylation step and the purification step in the manufacture of Iohexol. If the crude product obtained by the N-alkylation step is to be re-crystallised from a solvent that is different from the solvent used in the N-alkylation step, then the reaction solvent must first be removed e.g. by evaporation to dryness. It is known from crystallisation theory and experience that even small quantities of residual solvents from previous steps may cause a crystallisation process to get out of control due to changes in its supersaturating conditions, and thorough removal of the reaction solvent is an important step. Solvent removal is an energy consuming operation which also risks degradation of the product due to exposure to elevated temperature.

The process of preparation and purification of Iohexol according to the present invention shows several advantages with respect to the known processes. The process is made simpler because the purification and hydrolysis are, in practice, carried out in a single step. The yields of the hydrolysis reaction are practically quantitative and the reaction itself does not give rise by-products which otherwise very difficult to remove in the final stage. And overall yield of the process is very high and, above all, the purity characteristics of the resultant product completely as per pharmacopeias requirements. With the aim of better illustrating the present invention the following examples are now given.

Object of the Invention
An object of the present invention is to provide an improved process for the preparation of Iohexol of formula (1) and its intermediates.

Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of compound of formula (I)

which comprises the steps of:
i) nitration of isophthalic acid to obtain 5-nitro isophthalic acid;
ii) reduction of 5-nitro isophthalic acid to obtain 5-amino isophthalic acid (3);
iii) halogenation of 5-amino isophthalic acid to obtain 5-amino-2,4,6-triiodo isophthalic acid (5-ATIPA) (4);
iv) halogenation of 5-amino-2,4-6-triiodo isophthalic acid to obtain 5-ATIPA-dichloride;
v) N-acylation of 5-ATIPA-dichloride to obtain 5-acetamido-2,4,6-triiodoisophthaloyl dichloride (7);
vi) amidation of 5-acetamido-2,4,6-triiodoisophthaloyl dichloride to obtain 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (9);
vii) n-alkylation of the compound of formula (9) to obtain 5-[N-(2,3-dihydroxypropyl)acetamido]-N,N’-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide (Iohexol, compound of Formula 1);
viii) optionally,
(i) N-alkylation of the compound of formula (9) in presence of aqueous base to obtain compound of formula (11) and washing the compound of formula (11) with organic solvent;
(ii) protection of compound of formula (11) as acetal in the presence of ketone and organic solvent to obtain compound (12) or as ester in the presence of organic acid anhydride and organic solvent to obtain compound (12-A);
(iii) deprotection of compound (12) in the presence of acidic medium or deprotection of compound (12-A) in the presence of acidic or basic medium to obtain compound of formula (1).

The present invention includes within its scope, the compounds formed as part of the process, being:
1) 5-amino isophthalic acid (3).
2) 5-amino-2,4,6-triiodoisophthalic acid (4).
3) 5-acetamido-2,4,6-triiodoisophthaloyl dichloride(7).
4) 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (9)
5) N1,N3-bis(2,3-dihydroxypropyl)-5-(N-(2,3-dihydroxypropyl)acetamido)-2,4,6-triiodoisophthalamide (11).
6) N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl) acetamido)-5-(((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)glycyl)-2,4,6-triiodobenzamide (12).
7) ((5-(N-(2,3-diacetoxypropyl)acetamido)-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-3,1,2-triyl) tetraacetate (12-A).
8) 5-[N-(2,3-dihydroxypropyl)acetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide, Iohexol (1) with a very high purity of more than 99.59%.

Detailed Description of the Invention
The present invention relates to a process for the preparation of a polyhydroxy compound and salts and enantiomers thereof having formula I.

A preferred embodiment is illustrated in Scheme-2, 3 and 4 below.

The present invention relates to a novel process for the preparation of Iohexol and its intermediates.

The process of the present invention comprises:
i) nitration of isophthalic acid to obtain 5-nitro isophthalic acid;
ii) reduction of 5-nitro isophthalic acid to obtain 5-amino isophthalic acid;
iii) halogenation of 5-amino isophthalic acid to obtain 5-amino-2,4,6-triiodo isophthalic acid (5-ATIPA);
iv) halogenation of 5-amino-2,4-6-triiodo isophthalic acid to obtain 5-ATIPA-dichloride;
v) N-acylation of 5-ATIPA-dichloride to obtain 5-acetamido-2,4,6-triiodoisophthaloyl dichloride;
vi) amidation of 5-acetamido-2,4,6-triiodoisophthaloyl dichloride to obtain 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide;
vii) N-alkylation of the compound of (9) to obtain 5-[N-(2,3-dihydroxypropyl)acetamido]-N,N’-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide (Iohexol, compound of Formula 1);
viii) optionally,
(a) N-alkylation of the compound of formula (9) in presence of aqueous base to obtain compound of formula (11) and washing the compound of formula (11) with organic solvent;
(b) protection of compound of formula (11) as acetal in the presence of ketone and organic solvent to obtain compound (12) or as ester in the presence of organic acid anhydride and organic solvent to obtain compound (12-A);
(c) deprotection of compound (12) in the presence of acidic medium or deprotection of compound (12-A) in the presence of acidic or basic medium to obtain compound of formula (1).

The process of the present invention is described herein below in detail. The description is an embodiment of the present invention and may not be construed to limit the invention in any manner.

The various steps of the process of the present invention may be set out as below:
i. nitration of isophthalic acid to obtain 5-nitro isophthalic acid;
The nitration of Isophthalic acid may be conducted with any nitrating agents suitably with the mixtures of sulphuric acid nitric acid, sulphuric acid fuming nitric acid, only fuming nitric acid, oleum nitric acid, or oleum fuming nitric acid. The nitrating agent may be selected from the group mentioned above of sulphuric acid fuming nitric acid mixture preferably the fuming nitric acid along with sulphuric acid. The temperature of the reaction may be in the range of 20-100 deg. C, preferably 40-85 deg. C. The temperature may be held constant or may be increased in a phased manner. The reaction may be completed in a period of 15-48 hours. The 5-nitroisophthalic acid of the present invention may be obtained as a white solid.

ii. reduction of 5-nitro isophthalic acid to obtain 5-amino isophthalic acid;
The reduction of the nitro group of the 5-nitro isophthalic acid to convert to the amino group may be conducted by suitable reducing agents. This conversion may be conducted by reagents selected from the group comprising Iron metal acetic acid mixture, Iron metal con hydrochloric acid mixture, Iron metal formic acid mixture, preferably the reagent is Iron metal with acetic acid mixture. The reaction may need of a suitable catalyst to fast up the reaction. The catalyst may be selected from the group comprising oleum, sulphuric acid and Trifluoro acetic acid; preferably the catalyst is sulphuric acid. The reaction may be conducted at a temperature in the range of 60-100 deg. C, preferably in the range of 80-85 deg. C. The reaction may be completed in a time period of 4-10 hours, preferably 6-8 hours. The pH of the reaction may be in the range of 1-3 preferably about 2.

iii. halogenation of 5-amino isophthalic acid to obtain 5-amino-2,4,6-triiodo isophthalic acid (5-ATIPA);
The 5-amino isophthalic acid may be halogenated. The halogenation may be conducted by any suitable halogen, preferably the halogenation is iodination. The halogenation may be conducted with a suitable halogenating agent selected from the group comprising HICl2, NaICl2, KICl2, or ICl, preferably, the halogenating agent is HICl2. The reaction may be conducted at a temperature range of 40-80 deg. C, preferably in the range of 50-55 deg C. The reaction temperature may be raised in a phased manner. The reaction may be completed from 20-48 hours.

iv. halogenation of 5-amino-2,4-6-triiodo isophthalic acid to obtain 5-ATIPA-dichloride;
The 5-amino-2,4-6-triiodo isophthalic acid is halogenated so as to convert the acid to the acid chloride. The halogenation to convert the acid to the acid chloride may be conducted by using a suitable agent selected from the group comprising thionyl chloride, Oxalyl chloride and POCl3 preferably the reagent is thionyl chloride. The reaction may be conducted in presence of the solvent selected from the group comprising ethyl acetate, dichloromethane chloroform, toluene, DMF, preferably the solvent is DMF. The reaction may also contain the presence of phase transfer catalyst comprising TBAB, TBAC preferably TBAB . The reaction may be conducted at a temperature range of 50-100 deg. C, preferably in the range of 60-80 deg C. The product of the particular step being ATIPA-Cl may be purified using partition techniques.

v. N-acylation of 5-ATIPA-dichloride to obtain 5-acetamido-2,4,6-triiodoisophthaloyl dichloride;
The 5-ATIPA-dichloride may be N- acylated so as to convert the amino group to acetamide group. The N- acylation may be conducted with any suitable reagent selected from the group comprising acetic anhydride, acetylchloride, preferably, with acetyl chloride and the solvent may be selected from the group comprising mixtures of dimethyl acetamide/NMP, chloroform/NMP, dichloromethane/NMP, ethyl acetate/NMP or DMA alone and/or mixtures thereof, preferably the solvent is the mixture of DMA and NMP. The reaction may be conducted for a time period of 15-24 hours preferably 16-18 hours at a temperature of 0-30 deg C. The temperature may be raised in a phased manner and different reaction temperatures may be present in different conditions. The product of this step may be purified using fractionation techniques.

vi. amidation of 5-acetamido-2,4,6-triiodoisophthaloyl dichloride to obtain 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ;
The 5-acetamido-2,4,6-triiodoisophthaloyl dichloride may be amidated so as to have an amide linkage. The amidation may be conducted with 3-amino-1,2-propanediol to form diamide compound. The reaction may be conducted in presence of the solvent selected from the group comprising DMA, DMF, NMP, Tributylamine, Sodium Hydroxide, Lithium Hydroxide and NH4OH, or preferably DMA/NH4OH or DMF/NH4OH or mixtures thereof. The reaction may be conducted in the temperature range of 40-80 deg C. The reaction temperature may be changed in a phased manner. The reaction may take about 1-5 hours for completion.

vii. N-alkylation of the compound (9) to obtain 5-[N-(2,3-dihydroxypropyl)acetamido]-N,N’-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide (Iohexol, compound of Formula 1);
A compound of formula (9) 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, may be converted to iohexol of Formula 1 of the present invention by N-alkylation of the acetamide side chain. The N-alkylation may be conducted with 3-chloro-1,2-propanediol, the reaction may be conducted in a solvent selected from the group comprising 2-(2-methoxyethoxy) ethanol, propylene glycol or their mixtures. The reaction may be conducted at a temperature range of 10-30 deg C., preferably 18-25 deg C. The reaction mixture is treated with silica gel to remove the impurities. The compound of the present invention may be extracted by treating the silica gel with a solvent selected from the group comprising alcohol, preferably methanol. The reaction may be conducted at a pH of 3-5.

ix) Optionally, (a) N-alkylation of the compound of formula (9) in presence of aqueous base to obtain compound of formula (11) and washing the compound of formula (11) with organic solvent
A compound of formula (9) is converted to compound of formula(11) in the presence of aqueous base selected from the group comprising sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, more preferably sodium hydroxide and N-alkytaion with 3-chloro-1,2-propanediol. The reaction may also be conducted in a solvent selected from the group comprising 2-(2-methoxyethoxy) ethanol, propylene glycol or their mixtures. The reaction may be conducted at a temperature range of 10-30 deg C., preferably 18-25 deg C. The reaction mixture is treated with water and washed with chloroform or DCM to remove traces of organic solvents.

(b) protection of compound of formula (11) as acetal in the presence of ketone and organic solvent to obtain compound (12) or as ester in the presence of organic acid anhydride and organic solvent to obtain compound (12-A);
The compound of formula(11) to obation iohexol of formula (1) is protected as acetal in the presence of ketone such as acetone, catalytic amount of PTSA and organic solvent selected from the group comprising -(2-methoxyethoxy) ethanol, propylene glycol or their mixtures. The reaction may be conducted at a temperature range of 40-60 deg C., preferably 45-50deg C.
or the compound of formula (11) to obtain iohexol of formula(1) is protected as ester in the presence of organic acid anhydride such as acetic anhydride, catalytic amount of TFA. The reaction may be conducted at a temperature range of 35-40 deg C.

(c) deprotection of compound (12) in the presence of acidic medium or deprotection of compound (12-A) in the presence of acidic or basic medium to obtain compound of formula (1).
The compound of formula (12) can be deprotected in the presence of acid selected from the group comprising includes HCl, H2SO4, Acetic Acid, P-TSA. The reaction may be conducted at a temperature range of 55-70 deg C, preferably 60-65 deg C. A base may be used to adjust pH of the reaction mixture to neutral with base such as ammonium hydroxide.

The compound of formula (12-A) can be deprotected in the presence of acid selected from the group comprising includes HCl, H2SO4, Acetic Acid, P-TSA or a base selected from the group comprising ammonium hydroxide, sodium hydroxide. The reaction may be conducted at a temperature range of 55-70 deg C, preferably 60-65 deg C. A base may be used to adjust pH of the reaction mixture to neutral with base such as ammonium hydroxide.

In an aspect, the present invention includes within its scope, the synthesis and purifications of compounds:
The present invention includes within its scope, the compounds formed as part of the process, being:
1) 5-amino isophthalic acid (3).
2) 5-amino-2,4,6-triiodoisophthalic acid (4).
3) 5-acetamido-2,4,6-triiodoisophthaloyl dichloride(7).
4) 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (9)
5) N1,N3-bis(2,3-dihydroxypropyl)-5-(N-(2,3-dihydroxypropyl)acetamido)-2,4,6-triiodoisophthalamide (11).
6) N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl) acetamido)-5-(((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)glycyl)-2,4,6-triiodobenzamide (12).
7) ((5-(N-(2,3-diacetoxypropyl)acetamido)-2,4,6-triiodoisophthaloyl)bis(azanediyl))bis(propane-3,1,2-triyl) tetraacetate (12-A).
8) 5-[N-(2,3-dihydroxypropyl)acetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide, Iohexol (1) with a very high purity of more than 99.59%.

The process of the present invention yields Iohexol (1) with purity in the range of 99.38% to 99.59%, yield in the range of 85% to 87%. The process of the present invention decreases the reaction time by 24 hours to 3 hours in comparison to other prior art processes.

Without being limited by theory, the process of the present invention discloses that the usage of usage of protection in the final stage found and proved to be very advantageous as the all hydrophilic structural analogues of Iohexol will be completely washed away in water.

Without being limited by theory, the process of the present invention discloses that the usage of silica gel found to be very advantageous as the 60-120 mesh captures the non polar basic impurities and also binds the polar impurities otherwise which often soluble in an aqueous phase and creates problem in isolating them in purification of Iohexol in water and the process of the present invention also discloses that the usage of usage of protection in the final stage found and proved to be very advantageous as the all hydrophilic structural analogues of Iohexol will be completely washed away in water

Furthermore, the application discloses the unexpected advantage for using silica gel and DMA alcohol mixture to obtain Iohexol(1) with high purity. When Silica gel used in the reaction mixture itself, crude solid lohexol is dissolved in water, or if the aqueous solution is obtained directly from the reaction in which the lohexol is formed, any impurities being formed including unreacted starting material directly by filtration then 2-(2-methoxyethoxy) ethanol, propylene glycol and N-methyl pyrrolidine may be removed completely and Iohexol is obtained in a well defined crystalline form, in high purity. From an industrial point of view, this fact has obvious advantages. Furthermore, the process of the present invention is set out so as to obtain maximum yield and purity of Iohexol.

Furthermore, the application also discloses that the acetal of compound-12 is hydrolyzed in acidic media or ester of compound of formula 12-A in acidic or basic media to get directly a high pure Iohexol of formula (1) which needs no further purifications. However, OH group protection of Compound of formula 12 and formula 12-A to yield iohexol of formula (1) is crucial to remove to make any impurity to a minimum of 0.05% which ultimately gives a ultra pure Iohexol directly from the reaction mixture.

Advantages of the process of the present invention

1. Usage of Silica Gel for preparation and purification of Iohexol (1) and complete removal of O-alkylated impurities to obtain Iohexol (1) with a very high purity and optionally, the protection of OH group in the final stage to remove all hydrophilic structural analogues of Iohexol(1) in water purification of Iohexol (1) to obtain Iohexol (1) with a very high purity.
2. Complete elimination of the use of resins which renders the process of the present invention economical over other prior art processes and renders the process, industrially viable.
3. The process of the present invention eliminates the use of extremely toxic solvents that poses environmental threat and uses less hazardous chemicals.
4. Novel chemistry to achieve N-alkylation of diamide with ease, increased yield of the intermediate, with less impurities.

The following examples illustrate the process of the invention, without limitation. The examples are an embodiment of the present invention and may not be construed to limit the process of the present invention in my manner.

Example 1: Preparation of Iohexol(I)

Step 1- Preparation of 5-nitroisopthalic acid (2)

A suitable reaction vessel was charged with 1174.5 gm (11.745 mol) of sulfuric acid and 250 gm of isophthalic acid (1.506 mol) and mixed well for 1 hr at 25-30°C. Then the reaction mass was allowed to cool to 5-10°C, at this temperature, added 189 gm (3.00 mol) of fuming nitric acid slowly over about 90-120 min. During the addition, the temperature observed to be increased to40-45°C and held constant. Then slowly raised the temperature to 60°C-65°C and maintained at this temperature for 3 hrs. After that, the reaction mass temperature maintained at 80°C-85°C by gentle heating and stirred for 24h. After completion of the reaction by HPLC, (SM <1%) the reaction mass was allowed to RT and charged in to ice cold water and stirred for 60 minutes at 5°-10°C. The solid resulted was isolated by filtration and washed with chilled water and dried. Yield: (290.0 gm) 90.0% HPLC Purity 99.87%. (M+H) 212.23, IR (KBr): 3500 cm¯1, 1720 cm¯1, 1360-1290cm¯1, 1H-NMR: (300 MHz, DMSO-d6) d 12.8 (s, 2H), 8.2 (s, 3H), 13C-NMR (300 MHz-DMSO-d6): 164.1, 148.3, 135.2 133.4, 127.1

Step 2- Preparation of 5-aminoisopthalic acid (3):

A suitable reaction vessel was charged with 500 mL of DM Water, 250.0 gm (1.184 mol) of Compound (2), 1312 gr (21.8 mol) of acetic acid, 325.0 gm (1.184 mol) of iron 2.5 gm of sulfuric acid and mixed well. Slowly the reaction mass temperature was raised to 80 to 850C and stirred for about 5 hours. After completion of the reaction, it was allowed to RT, filtered off, collected the aliquot and set the pH less than 2 . Then it was stirred for 1 hour at 5 to 100C. The solid was isolated by filtration, washed with DM water and dried 3. Yield (204.0 gm) 95.0% with 97.8% of HPLC purity. (M+H) 182.5, IR (KBr): 3500 cm¯1 , 3020 cm¯1 , 1715cm¯1,; 1H-NMR: (300 MHz, DMSO-d6) d 13.1 (s, 2H), 8.2 (s, 3H), 6.23 (s, 2H) 13C-NMR (300 MHz-DMSO-d6); 167.4, 149.6. 134.3, 118.1 117.4.

Step 3-Preparation of 5- amino-2,4,6,triiodoisopthalic acid (5-ATIPA) (4):

A suitable vessel was charged with 8250 mL of DM water, 250.0 gm (1.381 mol) of 3 and mixed well. The temperature of the reaction mass was raised to 50°C-55°C, and then the reaction vessel was allowed by slow addition of 1126 gm (4.160 mol) of HICl2 solution about 3 hrs and stirred for about 24 h. When the reaction was completed by HPLC (SM<1%), it was allowed at RT and cooled to 0-5°C. The solid was isolated by filtration, washed with DM water and dried. Yield: (425.0 gm) 55.0% with 98.0 % of HPLC purity. (M+H) 559.84.; IR (KBr): 3500 cm¯1, 3020 cm¯1,; 1H-NMR:(300 MHz, DMSO-d6) d 13.6 (s, 2H), 7.23 (s, 2H).; 13C-NMR (300 MHz-DMSO-d6): 167.2, 139.2, 135.3, 97.3, 91.4.

Step4 - Synthesis of 5-aminotriiodo isophthaloyl dichloride (ATIPA-Cl) (5):

A suitable vessel was charged with 250 mL of DMF, 250 gm (0.447 mol) of 4 (ATIPA), 25.0 gm (0.0775 mol) of (TBAB) tertiary butyl ammonium bromide and followed by slow addition of 553.2 gm (4.648 mol) of thionyl chloride about 45 to 60 minutes. The temperature of reaction mass was raised to 750C and stirred for 24 h. After the complete consumption of starting material, the reaction mass was allowed to cool at 5- 10°C and quenched by water and extracted by ethyl acetate. The organic layer was separated and washed by saturated aqueous sodium bicarbonate solution, ammonium chloride and brine. The organic layer was separated dried over sodium sulfate, treated by charcoal and stirred for about 30 minutes at 40°C. Then the hot reaction mass was filtered off on celite bed and washed with ethyl acetate and distilled out to get 5, (5-ATIPA-Cl). Yield: (225.0 gr) 85.0 % with 96.0% of HPLC purity. (M+H) 596.9; IR (KBr): 3500 cm¯1 , 3020 cm¯1 , 1725cm¯1,; 1H-NMR: (300 MHz, DMSO-d6) d, 7.38 (s, 2H) 13C-NMR (300 MHz-DMSO-d6) 165.3, 148.3, 136.3, 95.2, 86.2.

Step 5- Synthesis of 5-acetamido-2,4,6-triiodoisophthaloyl dichloride (7)

A suitable vessel was charged with 125 mL of dimethyl acetamide (DMA) and 125 mL of N-methyl pyrrolidine 250 gm (0.419 mol) of 5 (ATIPA-Cl) and mixed well. The reaction mass was allowed to cool at 0-5°C, followed by slow addition of 34 gm (0.420 mol) of acetyl chloride 6 at 0 to 5°C for 50 to 60 min. Then it was allowed to RT and stirred for about 16-18 hr. When starting material was consumed (HPLC <1%), the reaction mass was extracted by ethyl acetate (1500 mL) and washed by water. The organic layer was separated and washed by 2% aqueous sodium bicarbonate solution, 5% ammonium chloride and brine solution. The organic layer was collected, dried over sodium sulphate, treated by charcoal and filtered off on celite bed. Finally the aliquot was distilled off to get desired compound of 7. Yield: (240.0gr) 90.0% with 96 % of purity. (M+H): 638.3; IR (KBr): 3100 cm¯1 , 3020 cm¯1, 1725cm¯1, 1685cm¯1 ,; 1H-NMR: (300 MHz, DMSO-d6) d 7.38 (s, 1H), 2.1 (s, 3H), 13C-NMR (300 MHz-DMSO-d6) 173.1, 172.3, 169.3, 147.3, 94.3, 83.4, 75.3, 26.4;

Step 6- Synthesis of 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(9)

A Suitable vessel was charged with 250 mL of dimethyl acetamide (DMA), 250 mL of N-methyl pyrrolidine and followed by addition of 300.0 gr of (3.0mol) of 17% ammonium hydroxide solution. The temperature of the reaction mass was raised to 45°C, then 80.08 gm (0.88 mol) of 3-amino,1,2-propanediol in 250mL of DMF solution was added slowly to same vessel at same temperature about 120 minutes. Then temperature of the reaction mass was raised to 65°C-70°C and stirred for about 2h. When the reaction was completed, distilled the solvents completely and reaction mass allowed to cool at RT and charged 1000 mL of DM water then pH 2.0 adjust with hydrochloric acid and filtered to get desired compound of 9. Yield: (220.0 gm) 75.0 % with 92.0% of HPLC purity. (M+H) 748.2 IR (KBr): 3100 cm¯1 , 3020 cm¯1, 1725cm¯1, 1685cm¯; 1H-NMR: (300 MHz, DMSO-d6) d, 7.41 (s 1H); 7.38 (s, 2H), 4.1(d,4H), 3.9(m,2H); 3.4(d 4H), 2.1(s 3H), 13C-NMR (300 MHz-DMSO-d6) 171.3, 170.8, 168.5, 147.1, 141.1,92.1, 87.3, 82.2, 78.4, 60.3, 57.4, 25.4, 21.1 .

Step 7 - Synthesis of 5-[N-(2,3-dihydroxypropyl)acetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-Triiodoisophtalamide (Iohexol 1):-

A suitable vessel was charged with 250 mL of 2-(2-methoxyethoxy) ethanol and 100 mL of propylene glycol, 250.0 gm (0.334 mol) of 9 and mixed well. The reaction mass allowed to cool at 18°C to 250C and charged 22 gm (0.528 mol) of Sodium hydroxide in 11 mL of DM Water to same vessel. The temperature of reaction mass was raised to 35 to 400C and stirred for about 120 minutes. Then the reaction vessel was added by 55.0 (0.5 mol) gm of 3-chloro 1,2 propanediol at RT about 30.0 minutes and charged 100 gm of silicagel,stirred for 3h at 65-72°C. When the reaction was completed, it allowed to cool at RT and added methanol. The reaction mass was adjusted to pH 4.5 and extracted with water and chloroform. The aqueous layer was collected and distilled out to get crude material of desired product 1. HPLC analysis (water/acetonitrile) of the Iohexol crude gave the following results: lohexol Purity: 99.02 %, 5-Acetamide: 0.06 %, O-alkylated substances: 0.58 %
Other impurities: 0.34 %,

Purification of IOHEXOL:
The crude product was added by NMP: Acetone: IPA (1:2:1) and stirred about 2 h at 0-5°C, finally the reaction mass was filtered off and collected the solid of desired pure compound of 1. Yield: (236.0 gm) 86.0%. After Purification Iohexol HPLC Purity, lohexol Purity: 99.66 %, 5-Acetamide:0.02 %, O-alkylated substances: 0.28 %, Other impurities: 0.04 %, (M+H) 822.4 IR (KBr): 3100 cm¯1 , 3020 cm¯1, 1685cm¯; 1H-NMR: (300 MHz, DMSO-d6) d 8.6 (s 1H), 7.88 (s, 1H), 4.4 (d, 6H), 3.94 (m, 6H), 3.6 (t 6H), 2.1( s 3H) 13C-NMR (300 MHz-DMSO-d6) 171.3, 170.8, 168.5, 147.1, 141.1,92.1, 87.3, 82.2, 78.4, 60.3, 57.4, 55.8 24.2.

Step 8: Optinally, (a) Synthesis of Iohexol Crude (11)

A suitable vessel was charged with 15 L of 2-(2-methoxyethoxy) ethanol and 15 L of propylene glycol, 10 kg of Compound (9) and mixed well and reaction mass allowed to cool at 18°C to 25°C. Then charged sodium hydroxide solution (800 gm of Sodium hydroxide dissolved in 2L of DM Water) while the temperature of reaction mass was kept at 40 to 450C with stirring about 4hrs. Then the reaction vessel was added by 2.0 kg of 3-chloro 1,2 propanediol at below RT about 1 hr and the reaction mass stirred for 26 hrs at 38-45°C. When the reaction completed, it was allowed to cool at RT. The reaction mass washed several times with 5 L of Chloroform and the aqueous layer was collected and distilled to get crude material of desired compound of 11. Yield: (10.4 kg) 95.0%. Purity by HPLC: 98.23%; and compound-A was about 0.80%. (RRT: 0.68)
(M+H) 822.4; IR (KBr): 3100 cm¯1 , 3020 cm¯1, 1685 cm¯1; HI-NMR: (300 MHz, DMSO-d6) d 8.6 (s 1H), 7.88 (s, 1H), 4.4 (d, 6H), 4.2 (m 3H),3.94 (m, 6H), 3.6 (t 6H), 2.1( s 3H); 13C-NMR (300 MHz-DMSO-d6) 171.3, 170.8, 168.5, 147.1, 141.1,92.1, 87.3, 82.2, 78.4, 60.3, 57.4, 55.8 24.2.

(b) Synthesis of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(((2,2-dimethyl-1,3-dioxolan-4-yl) methyl)glycyl)-2,4,6-triiodo-5-(N-((2-methyl-1,3-dioxolan-4-yl)methyl)acetamido)benzamide)(12)

A suitable vessel was charged with 100 L of Acetone and 6.0 L of 2, 2-dimethoxy propane, 500 gm of PTSA, 10.45 kg of compound (11) and mixed well. The temperature of reaction mass was kept at 45° to 50°C stirred for about 8 hrs. When the reaction completed, added 2 L methanol and distilled off then slurred with hot water to get desired compound of 12. Yield: 11.30 kg (95.0%) with 99.54 % purity.
(M+H) 942; IR (KBr): 3020 cm¯1 1685 cm¯1,1020 cm¯1; HI-NMR: (300 MHz, DMSO-d6) d 8.6 (s 2H), , 4.86 (d, 6H), 3.94 (m, 9H), 2.1( s 3H) ,1.8 ( s 18 H); 13C-NMR (300 MHz-DMSO-d6) 171.3, 170.8, 168.5, 147.1, 141.1,92.1, 87.3, 82.2, 78.4, 60.3, 57.4, 55.8,53, 24.2 ,15.

(c) Synthesis of Iohexol (1)

A suitable vessel was charged with 11.50 L of DM Water, 11.50 L of Con hydrochloric acid, 11.30 kg of compound (12) and mixed well. The temperature of reaction mass was kept 60° to 65°C and stirred for about 60 minutes. When the reaction completed, it was allowed to cooling at RT and washed with DCM/Chloroform. Then reaction mass pH was adjusted to neutral with ammonium hydroxide. Thus obtained aqueous layer was collected and completely distilled and dissolved in 4 L of isobutanol to get desired product of 1. Yield: 8.70 kg (88.0 %); HPLC purity: 99.76% and Compound-A: 0.03%. (RRT: 0.68).
(M+H) 822.4; IR (KBr): 3100 cm¯1 , 3020 cm¯1, 1685cm¯; HI-NMR: (300 MHz, DMSO-d6) d 8.6 (s 1H), 7.88 (s, 1H), 4.4 (d, 6H),4.2 (m 3H), 3.94 (m, 6H), 3.6 (t 6H), 2.1( s 3H); 13C-NMR (300 MHz-DMSO-d6) 171.3, 170.8, 168.5, 147.1, 141.1,92.1, 87.3, 82.2, 78.4, 60.3, 57.4, 55.8 24.2.
or
(a1)((5-(N-(2,3-diacetoxypropyl)acetamido)-2,4,6 triiodoisophthaloyl)bis(azanediyl))bis(propane-3,1,2-triyl) tetraacetate (Compound-12-A).

A suitable vessel was charged with 50 L of DMA, 100 gm DMAP, 10 kg of compound (11) and mixed well. The temperature of the reaction mass kept at 5° to 10° C and slowly adds 10 kg of acetic anhydride with catalytic amount of TFA. The reaction mass temperature rose to 35° to 40°C and stirred for about 8 hrs. When the reaction completed, added 2 L IPA and distilled off then slurred with hot water to get desired compound of 12-A. Yield: 10.46 kg (80 %) with 99.57 % purity.
(M+H) 1074; IR (KBr): 3020 cm¯1 1740 cm-1 1685 cm¯1,1020 cm¯1; HI-NMR: (300 MHz, DMSO-d6) d 8.6 (s 2H), , 4.86 (d, 6H), 4.14 (m, 3H), 3.8 (d, 6H); 2.1( s 21H). 13C-NMR (300 MHz-DMSO-d6): 171.3, 170.8, 168.5, 147.1, 141.1, 92.1, 87.3, 82.2, 78.4, 60.3, 57.4, 55.8,53, 24.2, 15.1.

(b2) Synthesis of Iohexol(1)

A suitable vessel was charged with 11.50 L DM Water, 13.50 L of 15% Ammonium hydroxide, 10.46 kg of compound (12-A) and mixed well. The temperature of reaction mass was kept 60° to 65°C and stirred for about 9 hrs. When the reaction completed, it was allowed to cooling at RT and washed with DCM/Chloroform. Then reaction mass pH was adjusted to neutral and thus obtained aqueous layer was collected and completely distilled and dissolved in 4 L of isobutanol to get desired product of 1. Yield: 7.01 kg (80%); HPLC purity: 99.66%. Compound-A: 0.0.6% (RRT: 0.68)
(M+H) 822.4; IR (KBr): 3100 cm¯1 , 3020 cm¯1, 1685cm¯; HI-NMR: (300 MHz, DMSO-d6) d 8.6 (s 1H), 7.88 (s, 1H), 4.4 (d, 6H), 4.2 (m 3H),3.94 (m, 6H), 3.6 (t 6H), 2.1( s 3H); 13C-NMR (300 MHz-DMSO-d6) 171.3, 170.8, 168.5, 147.1, 141.1,92.1, 87.3, 82.2, 78.4, 60.3, 57.4, 55.8 24.2.

(b3) (Synthesis of Iohexol(1)

A suitable vessel was charged with 11.50 L DM Water, 13.50 L of Con. HCl, 11.45 kg of compound (12-A) and mixed well. The temperature of reaction mass was kept 60° to 65°C and stirred for about 12 hrs. When the reaction completed, it was allowed to cooling at RT and washed with DCM/Chloroform. Then reaction mass pH was adjusted to neutral and thus obtained aqueous layer was collected and completely distilled and dissolved in 4 L of isobutanol to get desired product of 1.
Yield: 7.89 kg (82%); HPLC purity: 99.59% and Compound-A: 0.07% (RRT: 0.68)
(M+H) 822.4; IR (KBr): 3100 cm¯1 , 3020 cm¯1, 1685cm¯; HI-NMR: (300 MHz, DMSO-d6) d 8.6 (s 1H), 7.88 (s, 1H), 4.4 (d, 6H), 4.2 (m 3H), 3.94 (m, 6H), 3.6 (t 6H), 2.1( s 3H); 13C-NMR (300 MHz-DMSO-d6) 171.3, 170.8, 168.5, 147.1, 141.1,92.1, 87.3, 82.2, 78.4, 60.3, 57.4, 55.8 24.2.

Example 2: Comparison of the process of the present invention again prior art processes.
The process of the present invention is advantageous over other processes listed in the prior art. Comparison of the process of the present invention over other processes of prior art are listed herein below at Table 1:

Table 1: Comparison of the process of the present invention over the processes of prior art.
S.No Patent No Conditions Yield Conclusion
1 WO 9808804 This patent discloses N-alkylation reaction with methoxy ethanol as a solvent in Sodium hydroxide. The total reaction hours for amidification with an alkyl halide 30 hrs. And also Purification disclosed with methoxy ethanol and mixtures thereof with isopropanol are used both in Iohexol. It’s found to be, the examples provided shown that the technique is scarcely effective in eliminating the O-alkylate impurities. Not given The solvent methoxyethanol is highly dangerous can cause damages to the reproductive system, sterility and foetal malformations. It’s found to be very difficult to remove this solvent due to its high boiling point and hydrophilic nature in the final Iohexol thus makes the process unfavorable for manufacturing.
2 US 5,204,086
This patent disclosed only purification where the crystallization with isopropanol is effective in eliminating the O-alkylate impurities from Iohexol only by 25 to 30%. Practically it’s been found isopropanol alone is not capable to remove impurities substantially as disclosed in the patent. 62% This process is commercially unviable.
3 EP 919540 This patent describes the crystallization with Ethanol to reduce the O-alkylated impurities. Nevertheless, the examples provided shown the best case, from 1% initial content to just slightly lowered and set to 0.58%. The purification value thus obtained is just lower side of limit fixed by EP and US Pharmacopea. Not given The said method and technique is not completely effective in eliminating O-alkylated impurities. Thus makes the process unfavorable for manufacturing.
4 US 4,250,113
US 7,541,494 This patent discloses N-alkylation reaction in a basic environment with amide and alkyl halide in 48-52 hrs. The purification done with Amberlite and Dowex resin and followed by butanol purification at -20° C. 52% The said method has a very long duration for the N-alkylation step. Furthermore the process utilizes several resins and very low temperatures. These conditions render the process unattractive in terms of cost and time and scalability.

05.
EP1641743
This patent described Iohexol purification was performed by anionic and cationic ion exchange resins and crystallization from 1-methoxy -2-propanol.
88% It was observed like ethanol, the 1-methoxy-2-propanol cannot alone remove all the process impurities in Iohexol preparation and also several resin purifications needs to be done. Hence, this process is not good for commercialization.
6 PROCESS OF THE PRESENT INVENTION The present invention discloses N-alkylation reaction in mixture of solvents in aqueous alkali and with Silica gel in 2 hrs. And also the purification of the crude product is involving NMP: Acetone: IPA (1:2:1) for 2 h at 0-5°C results in a highly pure crystalline compound and novel modification in procedure of Iohexol synthesis which substantially removes all theof listed impurities and process impurities found in Iohexol multi step synthesis.
86 to 89% The process of the present invention yields Iohexol of purity in the range of 99.38% to 99.49%, decreases time by 24 to 3 hours, the yield of the processes is in the range of 85 to 87%. In order to overcome the problem in attaining high purity of Iohexol as per pharmacopeia the procedure which is disclosed is a most suitable and convenient for multi ton production. Simple chemical process by all impurities can be removed very easily. This process proved to be very robust and economical and has high commercial value.

,CLAIMS:1. A process for the preparation of polyhydroxy compound of formula (1) and intermediates thereof

Comprising the steps of:
i) Nitration of isophthalic acid to obtain 5-nitro isophthalic acid of formula (2);

ii) Reduction of 5-nitro isophthalic acid of formula (2) to obtain 5-amino isophthalic acid of formula (3);

iii) Halogenation of 5-amino isophthalic acid of formula (3) to obtain 5-amino-2,4,6-triiodo isophthalic acid (5-ATIPA) of formula (4);

iv) Halogenation of 5-amino-2,4-6-triiodo isophthalic acid of formula (4) in presence of acid chloride, solvent, optionally phase transfer catalyst to obtain 5-ATIPA-dichloride of
formula (5);

v) N-acylation of 5-ATIPA-dichloride of formula (5) to obtain 5-acetamido-2,4,6-triiodoisophthaloyl dichloride of formula (7);

vi) Amidation of 5-acetamido-2,4,6-triiodoisophthaloyl dichloride of formula (7) in presence of a solvent to obtain 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide of formula (9);

vii) N-alkylation of the compound of formula (9) in presence of aqueous base to obtain compound of formula (11) and washing the compound of formula (11) with organic solvent;

viii) Protection of compound of formula (11) as acetal in the presence of ketone and organic solvent to obtain compound (12) or as ester in the presence of organic acid anhydride and organic solvent to obtain compound (12-A);

ix) Deprotection of compound (12) in the presence of acidic medium or deprotection of compound (12-A) in the presence of acidic or basic medium to obtain compound of formula (1);

x) Optionally, N-alkylation of the compound of formula (9) with 3-chloro-1,2-propanediol in presence of organic solvent and purification with acetone to obtain 5-[N-(2,3-dihydroxypropyl)acetamido]-N,N’-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophtalamide of formula (1).

2. The process as claimed in claim 1 wherein, the nitrating agent used in step (i) may be selected from the group comprising mixtures of sulphuric acid nitric acid, sulphuric acid fuming nitric acid, only fuming nitric acid, oleum and nitric acid, or oleum and fuming nitric acid, preferably mixture of fuming nitric acid along with sulphuric acid.

3. The process as claimed in claim 1 wherein, the reducing agent used in step (ii) may be selected from the group comprising Iron metal acetic acid mixture, Iron metal con hydrochloric acid mixture, Iron metal formic acid mixture, preferably Iron metal with acetic acid mixture and the catalyst may be selected from the group comprising oleum, sulphuric acid and trifluoro acetic acid, preferably sulphuric acid.

4. The process as claimed in claim 1 wherein, the halogenation in step (iii) may be may be conducted by any halogen, preferably the iodination with halogenating agents selected from the group comprising HICl2, NaICl2, KICl2, or ICl, preferably HICl2 and the halogenations in step (iv) May be conducted by using a suitable agent selected from the group comprising thionyl chloride, Oxalyl chloride and POCl3, preferably the thionyl chloride.

5. The process as claimed in claim 1 wherein, the acid chloride used in step (iv) may be selected from the group comprising thionyl chloride, oxalyl chloride, preferably the thionyl chloride and the solvent used in step (iv) may be selected from the group comprising ethyl acetate, dichloromethane chloroform, toluene, DMF, preferably the DMF and phase transfer catalyst in step (iii) may be selected from the group comprising TBAB, TBAC, preferably TBAB.

6. The process as claimed in claim 1 wherein, the acylating in step (v) may be conducted with reagent selected from the group comprising acetic anhydride, acetylchloride, preferably, with acetyl chloride and the solvent may be selected from the group comprising mixtures of dimethyl acetamide/NMP, chloroform/NMP, dichloromethane/NMP, ethyl acetate/NMP or DMA alone and/or mixtures thereof, preferably, the mixture of DMA and NMP.

7. The process as claimed in claim 1 wherein, the solvent used in step (vi) may be selected from the group comprising DMA, DMF, NMP, Tributylamine, Sodium Hydroxide, Lithium Hydroxide and NH4OH, preferably DMA/NH4OH or DMF/NH4OH or mixtures thereof.

8. The process as claimed in claim 1 wherein, the aqueous base used in step (vii) may be selected from the group comprising sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, more preferably sodium hydroxide and the solvent used in step (vii) may be selected from the group comprising 2-(2-methoxyethoxy) ethanol, propylene glycol or their mixtures.

9. The process as claimed in claim 1 wherein, ketone used in step (viii) may be selected from the group comprising acetone, THF, Benzyl bromide and organic acid anhydride Acetyl chloride used in step (viii) may be selected from the group comprising acetic anhydride.

10. The process as claimed in claim 1 wherein, acid used in step (ix) may be selected from the group comprising, All mineral acids, Acetic Acid, p-TSA and base used in step (ix) may be selected from the group comprising ammonium hydroxide and alkali metal hydroxides, preferably ammonium hydroxide.
11. The process as claimed in claim 1 wherein, the organic solvent used in step (x) and (viii) may be selected from the group comprising 2-(2-methoxyethoxy) ethanol, propylene glycol or their mixtures.

12. The process as claimed in claim 1 wherein, the reaction of step (ii) is carried out maintaining the pH in range of 1-3, preferably less than 2.

13. The process as claimed in claim 1 wherein, the reaction of step (vii) is carried out maintaining the pH less than 5, more preferably less than …, and most preferably less than

14. A novel compound of formula (5), formula (7), formula (9), formula (11), formula 12 or (12-A)