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 Iopamidol and its intermediates.
Background of the Invention
Iopamidol (1) is chemically known as L-5-(2-hydpoxypropionylamino)-2,4,6-triiodoisophthalic acid bis-(1,3-dihydpoxypropylamide). Iopamidol is used in diagnostics as X-ray non-ionic contrast and belongs to chemical class of iodobenzenes. Iopamidol is administered at high doses in diagnostics and therefore it is required to synthesize this product in high purity.

A number of processes are known in prior arts for the preparation of Iopamidol. One of the first disclosures of process of preparation of Iopamidol was disclosed in British Patent No. 1,472,050. The synthesis of Iopamidol disclosed in British Patent No. 1,472,050 comprises of the following steps:
A) preparation of 5-amino-2,4,6-triiodoisophthalic acid by iodination of 5-aminoisophthalic acid; B) preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride; C) reaction of 5-amino-2,4,6-triiodoisophthalic acid dichloride with L-2-acetoxypropionic acid chloride to give L-5-(2-acetoxypropionylamino)-2,4,6-triiodoisophthalic acid dichloride(compound A);
D) Reaction of compound A with 2-amino-1,3-propanediol in an aprotic solvent, usually dimethylacetamide, and in the presence of a base to obtain L-5-(2-acetoxypropionylamino)-2,4,6-triiodoisophthalic acid bis-(1,3-dihydroxypropylamide) (compound B);
E) Basic hydrolysis of compound B to obtain crude Iopamidol followed by purification of crude iopamidol by de-salting through resins and subsequent series of crystallization.
However, the purification step of the crude Iopamidol is particularly long and difficult because the purity requirements of Iopamidol must be extremely high and, in the meantime, the impurities in the product are difficult to be separated moreover involves the use of weak anionic resins which are not capable enough to pick all the impurities and does not yield a very pure product.

U.S. Patent No. 4,001,323 describes a process for preparing iopamidol which involves:

a) reacting 5-amino-2,4,6-triiodoisophthalyl dichloride (ATIPA-Cl) with 2(S)-acetoxypropionyl chloride to form an acetyl-amide intermediate;
b) reacting the acetyl amide intermediate with serinol to provide acetyliopamidol;
c) reacting the acetyliopamidol with an aqueous base, such as, sodium hydroxide to hydrolyze the ester and provide iopamidol.
The product is purified by ion exchange resins, followed by recrystallization from ethanol. Ion exchange treatment used in US ‘323 is inappropriate for scale up and industrial application.

U.S. Patent No. 4,352,788 describes another process for preparation of N- alkyalted iopamidol derivatives. The products are isolated by counter-current extraction. However it utilizes the hazardous solvents and the basic hydrolysis induces racemization in product which does not correspond to USP specification for specific rotation value.

U.S. Patent No. 4,396,598 discloses a method for preparing N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisophthalimide. This patent also discloses the preparation of iopamidol starting with ATIPA-Cl. However, the polyhydroxy product was purified via preparative liquid chromatography which inevitably leads to a very high production cost and is not suitable for scale up or industrial application.

U.S. Patent No. 5,204,005 discloses the use of a reverse phase chromatographic process for purification of water soluble, non-ionic contrast medium compounds.

US Patent No. 5,550,287 describes the use of strong and weak anionic resins along with column chromatography to purify Iopamidol. Moreover, the process in this patent utilizes acetic acid as eluent which inevitably may lead to high chance of o-acetyl impurities generation with freely available OH groups of Iopamidol.

U.S. Patent No. 6506938 and W095/04031 describes the purification of Iopamidol in 2-butanol and removal of water in the molecule by azeotropic distillation with toluene.
European Patent 0747344 describes the use of n-propanol and isopropanol for purification. Although, it discloses very high purity and high yields but the experiments are performed on 30 gm scale which is not reproducible on commercial scale.

Further, IP2016/41010541 describes the usage of silica gel and DMA alcohol mixture solves these problems. It discloses silica gel along with reactants in one pot while (S)-Acetoxy Serninolamide (9) converts in to Iopamidol in water/IPA mixture where any impurities being formed including unreacted starting material will go directly by filtration IPA/DMA mixture Iopamidol from the solution in a well defined form. From an industrial point of view, the use of silica gel usage to carry out the purification of lopamidol provides a good industrial scale process.

The process fails when applied in multi tons preparation using the same conditions and is found to be a little practical advantages. When this procedure is applied to the bulk scale production; it is found that the silica gel does not give any useful advantages. Moreover, loading of silica gel equally increases with respect to increasing batch size which creates another problem to remove silica gel completely from the reaction which obviously makes the process of little commercial value.

US Patent No. 7,282,607 discloses the process of preparation iopamidol which involves the step of deacylation wherein all of the hydroxy groups of Iopamidol have been acylated. However, this method still has a problem in eliminating o-acetyl compound by hydrolysis. The o-acetyl is a major impurity which cannot be removed once the iopamidol is formed. This patent also covers an additional step for purification utilizing resins, which is impractical while scaling up the process.

The process of prior art involves either usage of strong resins or other available chromatographic techniques including preparative chromatography to eliminate the amounts of by-products and impurities and do not result into high purity of the compound.
Hence, there is a need of an improved process of purification of Iopamidol in order to overcome the problems of the prior art which results in high yield, free from any by-products and having the purity characteristics of the resultant product completely as per pharmacopeias requirements.

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

Summary of the Invention
The present invention provides an improved process for the preparation of polyhydroxy compound of Formula (I) and intermediates thereof:

which comprises the steps of:
(a) preparation of 5-amino-2,4,6-triiodoisophthalic acid (5-ATIPA) (4)
i. by selective nitration and subsequent reduction of isophthalic acid to obtain 5-amino isophthalic acid (3) in presence of nitrating and reducing agent.
ii. iodination of 5-amino isophthalic acid (3) to obtain 5-amino-2,4,6-triiodoisophthalic acid(5-ATIPA) by iodinating agent.
(b) preparation of iopamidol (1) from 5-amino-2,4,6-triiodoisophthalic acid (5-ATIPA)
i) reaction of 5-amino-2,4,6-triiodoisophthalic acid with thionyl chloride and phase transfer catalyst to obtain 5-ATIPA chloride (5).
ii) reaction of 5-ATIPA Cl (5) with 1 eq. 2(S)-acetoxy propionyl chloride (6) and DMA (dimethyl acetamide) to obtain (S)-1-((3, 5 bis (chlorocarbonyl)-2, 4, 6-triiodophenyl) amino-1-oxopropan-2-yl (7)
iii) reaction of compound of formula (7) with 2 eq. of 2-amino1,3 dihydroxy propane (8) in presence of amine solvent to obtain (S)- acetoxy serinolamide (9).
iv) hydrolysis of acetyl compound (9) in presence of aqueous base and silica gel to remove o- acetyl impurities to obtain crude Iopamidol(1)
(c) purification of Iopamidol
purification is performed utilizing DMA and organic solvent to obtain pure Iopamidol.
final purification is carried out with silica gel and ethanol to obtain highly pure Iopamidol.

(d) optionally,
i) hydrolysis of (S)- acetoxy serinolamide (9) to obtain compound of Iopamidol (10) with demineralised water in presence of base;
ii) protection of Iopamidol (10) to obtain iopamidol acetal compound-11 using ketone or to obtain acetyl iopamidol (11-A) using organic acid anhydride; and
iiii) deprotection of iopamidol acetal compound-11 with demineralised water in presence of acid to obtain Iopamidol (1) or deprotection of acetyl iopamidol (11-A) with demineralised water in presence of base to obtain Iopamidol (1) and purification of Iopamidol (1) using DMA and organic solvents to obtain pure Iopamidol (1)

provided that both deprotection and purification occur in a single step and no resins or no additional purification steps required.

The above process is illustrated in the following schemes 1, 1-A and I-B:
Scheme 1

Scheme 1-A

Scheme 1-B

Detailed Description of the Invention
The present invention provides an improved process for the preparation of Iopamidol of formula (1) and intermediates comprising:
(A) preparation of 5-amino-2,4,6-triiodoisophthalic acid (5-ATIPA) (4)
a) by selective nitration and subsequent reduction of isophthalic acid to obtain 5-amino isophthalic acid (3) in presence of nitrating and reducing agent.
b) iodination of 5-amino isophthalic acid (3) to obtain 5-amino-2,4,6-triiodoisophthalic acid(5-ATIPA) by iodinating agent.
(B) preparation of iopamidol (1) from 5-amino-2,4,6-triiodoisophthalic acid (5-ATIPA)
(i) reaction of 5-amino-2,4,6-triiodoisophthalic acid with thionyl chloride and phase transfer catalyst to obtain 5-ATIPA chloride (5).
(ii) reaction of 5-ATIPA Cl (5) with 1 eq. 2(S)-acetoxy propionyl chloride (6) and DMA (dimethyl acetamide) to obtain (S)-1-((3, 5 bis (chlorocarbonyl)-2, 4, 6-triiodophenyl) amino-1-oxopropan-2-yl (7)
(iii) reaction of compound of formula (7) with 2 eq. of 2-amino1,3 dihydroxy propane (8) in presence of amine solvent to obtain (S)- acetoxy serinolamide (9).
(iv) hydrolysis of acetyl compound (9) in presence of aqueous base and silica gel to remove o- acetyl impurities to obtain crude Iopamidol(1).
(C) purification of Iopamidol
purification is performed utilizing DMA and organic solvent to obtain pure Iopamidol.
final purification is carried out with silica gel and ethanol to obtain highly pure Iopamidol.

(D) optionally,
i. hydrolysis of (S)- acetoxy serinolamide (9) to obtain compound of Iopamidol (10) with demineralised water in presence of base;
ii. protection of Iopamidol (10) to obtain iopamidol acetal compound-11 using ketone or to obtain acetyl iopamidol (11-A) using organic acid anhydride; and
iii. deprotection of iopamidol acetal compound-11 with demineralised water in presence of acid to obtain Iopamidol (1) or deprotection of acetyl iopamidol (11-A) with demineralised water in presence of base to obtain Iopamidol (1) and purification of Iopamidol (1) using DMA and organic solvents to obtain pure Iopamidol (1)

provided that both deprotection and purification occur in a single step and no resins or no additional purification steps required

Preparation of 5-amino-2,4,6-triiodoisophthalic acid (5-ATIPA) (4)
Isopthalic acid may be converted to 5-amino isopthalic acid by selective nitration and subsequent reduction in presence of nitrating and reducing agent in step (a).

The nitrating agent used in step (a) may be selected from the group comprising combination of HNO3 with H2SO4, NaNO3 with H2SO4 and KNO3 with H2SO4. Preferably the nitrating agent is combination of HNO3 and H2SO4 preferably in a ratio of 0.1 to 3.5, more preferably 0.5 to 3.0, and most preferably 1.0 to 2.3.
The reducing agent used in step (a) may be selected from group comprising combination of sodium sulphide with NaHCO3, sodium bisulfate with NaHCO3, sodium thiosulphate with NaHCO3, sodium bis(2-methoxyethoxy)aluminumhydride with NaHCO3, sodium borohydride with NaHCO3, sodium cyanoborohydride with NaHCO3, sodium dithionite with NaHCO3, sodium hydrosulfite with NaHCO3, sodium hydroxymethanesulfinate with NaHCO3, sodium tetrahydroborate with NaHCO3, sodium triacetoxyborohydride with NaHCO3. Preferably the reducing agent is combination of sodium sulphide and NaHCO3 preferably in a ratio of 0.1 to 3.0, more preferably 0.5 to 2.0 and most preferably 1.0 to 1.65.
The reaction of step (a) temperature after addition of sulphuric acid is maintained at 35-40oC, more preferably 30-35oC, and most preferably 25-30oC for 1 hour.

The reaction of step (a) addition of nitric acid may be preferably carried out at 50-55oC, more preferably 45-50oC, and most preferably 40-45oC in 80 -130 min, preferably 90-120 min.
The reaction of step (a) temperature after addition of nitric acid may be preferably maintained at 70-75oC, more preferably 65-70oC, and most preferably 60-65oC for 4 hours, preferably 3 hours.
The reaction of step (a) temperature during nitration may be preferably maintained at 70-95oC, more preferably 75-90oC, and most preferably 80-85oC for 24 hours.
The reaction of step (a) reduction may be preferably carried out at 70-95oC, more preferably 75-90oC, and most preferably 80-85oC for 5 hours.
The reaction of step (a) pH after completion of reduction may be preferably maintained less than 4, more preferably less than 3, and most preferably less than 2.
The reaction of step (a) stirring after completion of reduction may be preferably carried out at 15-20oC, more preferably 10-15oC, and most preferably 5-10oC for 10 hours.
The process of the present invention wherein in step (b) comprises iodination of compound of formula (3) to obtain 5-amino-2,4,6-triiodoisophthalic acid(5-ATIPA)(4) with iodinating agent and water.
The process of the present invention wherein the said iodinating agent of step (b) may be selected from group comprising I2 (molecular iodine), ICl(Iodine chloride), NIS (N-Iodosuccinimide), NaCl2(Sodium dichloroiodate), KICl2(Pottasium dichloroiodate), more preferably NaCl2.
The reaction of step (b) addition of NaICl2 may be preferably carried out in 5 hours, more preferably 4 hours, and most preferably 3 hours.
The reaction of step (b) iodination may be preferably carried out at 40-65 oC, more preferably 45-60oC, and most preferably 50-55oC for 24 hours.

Preparation of Iopamidol from 5-amino-2,4,6-triiodoisophthalic acid (5-ATIPA) (1)
The process of the present invention wherein in step (i) comprises reaction of compound of formula (4) in presence of thionyl chloride and phase transfer catalyst.
The reaction of step (i) addition of thionyl chloride may be preferably carried out in 35-70 min, more preferably 40-65 min, and most preferably 45-60 min.

The phase transfer catalyst may preferably be selected from the ammonium bromide group comprising tetrabutylammonium bromide, tetraethylammonium bromide, tetramethylammonium bromide, trimethylvinylammonium bromide, tetrapropylammonium bromide, tetradecyltrimethylammonium bromide, tetraamylammonium bromide, tetrahexylammonium bromide, tetraheptylammonium bromide, tetra-n-octylammonium bromide, trimethylphenylammonium bromide, more preferably tetrabutylammonium bromide.

The reaction of step (i) temperature of reaction may be preferably maintained at 95oC, more preferably 85oC, and most preferably 75oC for 36 hours.
The process of the present invention wherein in step (ii) comprises reaction of compound of formula (5) with 1 eq. 2(S)-acetoxy propionyl chloride (6) and DMA (dimethyl acetamide).
The reaction of step (ii) addition of 2(S)-acetoxy propionyl chloride may be preferably carried out in 30-80 min, more preferably 40-70 min, and most preferably 50-60 min.
The reaction of step (ii) reaction mass may be stirred at RT for 20-22 hours, more preferably 18-20 hours, and most preferably 16-18 hours.
The process of the present invention wherein in step (iii) comprises reaction of compound of formula (7) in DMA and acetonitrile with serinol (8) in presence of organic base.
The reaction of step (iii) addition of serinol may be preferably carried out in 140 min, more preferably 130 min, and most preferably 120 min at 45 oC.
The organic base may be selected from the group comprising trimethylamine, tributylamine, triethylamine, tripropylamine, pyridine, piperidine more preferably tributylamine.
The reaction of step (iii) temperature of reaction mass may be preferably maintained at 110-120oC, more preferably 100-110oC, and most preferably 90-100oC for 5 hours.
The reaction of step (iii) may be cool at RT, extracted with DM water and DCM, aqueous layer is collected and treated with charcoal, filtered on celite bed and distilled off solvent to obtain compound of formula (9).
The process of the present invention wherein in step (iv) comprises hydrolysis of compound of formula (9) in presence of aqueous base and silica gel to obtain compound of formula (I).
The aqueous base used in step (iv) may be selected from group comprising sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, more preferably sodium hydroxide.
The reaction of step (iv) during hydrolysis may be carried out at 35-40 oC , more preferably 30-35oC, and most preferably 25-30oC for 120 min.
The reaction of step (iv) pH of reaction may be maintained at 5 and cooled at 15-20oC, more preferably 10-15oC, and most preferably 5-10oC followed by addition of silica gel and stirred for 2 hours.
The reaction of step (iv) reaction mass may be filtered, washed with water and distilled to obtain desired compound of formula (1).

Purification of Iopamidol
The crude Iopamidol obtained from step (iv) may be dissolved in DMA at 85 oC and stirred for 3 hours and further washed and filtered.
The filtrate obtained may further dissolved in suitable organic solvent and stirred at 90 0C for 6 hours, cooled and collected wet cake was transferred to premixed Acetonitrile/IPA/ methanol (1:1:1) stirred for 1 hour filtered and dried.
The organic solvent may preferably be selected from the group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, tertiary butyl alcohol, acetone, ethyl acetate, and the like or combination of above solvents, more preferably isopropyl alcohol.

The Iopamidol obtained may further be dissolved in DMA/ Water (1:1) ratio and stirred for 3 hours at appropriate temperature.
The stirring may be carried out at 40-45 0C, more preferably 35-40 0C, and most preferably 30-35 0C. Then silica gel (60-120) and DMA may be added, cooled at 7-10 0C, more preferably 6-9 0C, and most preferably 5-7 0C and stirred for 2 hours.
Followed by distillation and reflux the reaction mass with ethanol for 5 hours, cooled, washed and dried to obtain highly pure Iopamidol.

Optionally, the process of the present invention wherein in step (iv) comprises hydrolysis of compound of formula (9) in presence of aqueous base and dimeralised water to obtain compound of formula (10)
The aqueous base used in step (iv) may be selected from group comprising sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, more preferably sodium hydroxide.

The process of the present invention wherein in step (v) comprises protection of all available OH groups of compound of formula (10) as acetals may be conducted using ketones selected from the group comprising acetone, THF, Benzyl bromide, preferably, acetone to form compound of formula (11) or as esters using organic acid anhydride selected from the group comprising acetic anhydride, Acetyl chloride; preferably acetic anhydride to form compound of Formula (11-A).

The process of the present invention wherein in step (vi) deprotection of compound of formula (11) with demineralised water in presence of acid selected from the group comprising All mineral acids, hydrochloric acid, trifluoroacetic acid, or a combination thereof, preferably hydrochloric acid, trifluoroacetic acid or a combination thereof to obatin compound of formula (1) or deprotection of compound of formula (11-A) with demineralised water in presence of base selected from the group comprising ammonium hydroxide, and alkali metal hydroxides, preferably ammonium hydroxide to obatin compound of formula (1) purification of compound of formula (1) using DMA/chloroform and organic solvent may preferably be selected from the group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, tertiary butyl alcohol, acetone, ethyl acetate, and the like or combination of above solvents, more preferably isopropyl alcohol, provided that both deprotection and purification occur in a single step and no resins or no additional purification steps required

In one embodiment, the present invention also provides a novel compounds of Formula compound -11 and compound 11-A formed by the process of the present invention.

Without being limited by the theory, the process of the present invention provides a novel and efficient process for the preparation of Iopamidol of formula 1and intermediates thereof of formula 11 and formula 11-A. The process of the present invention involves the use of sodium sulphide and sodium bicarbonate for reduction avoiding the use of metal and heterogeneous catalyst which takes longer hours to complete reaction and makes unfavourable for commercial scale up. The process of the present invention involves the protection of all available OH groups in formula (10) as acetals and esters solve the problem of the prior art. The present invention simplifies the purification by introducing a novel step to get directly high pure material without using any resins or additional purifications. The present invention also facilitate to remove the all impurities including unreacted starting material which directly goes in to water and subsequently isolated material is high pure and meet the requirements of pharmacopeias standards. Therefore, the use of protection of OH groups in the compound of Formula (10) as acetals and esters and subsequent deprotection will substantially facilitate the multi ton production of the material.

Advantages of the present invention:
1. The novel acetal and acetate esters protection of crude Iopamidol provides complete elimination of from o-alkylated and o-acetyl impurities and a very high purity and Standard Optical Rotation of more than -5.09° by completely eliminating resins.

2. The present invention provides environmentally less polluting, high purity & high chemical yield of the final pharmaceutically active product leading to a low cost of production.

The invention is now described in detail with reference to the following examples; however, the following examples should not be construed as limiting the scope of the present invention in any way.

Example 1: Preparation of 5-nitroisopthalic acid (2):

A suitable reaction vessel was charged with 1174.5 gm (11.745 mol) of sulphuric 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 512.75 gm (5.932 mol) of concentrated nitric acid (78%) slowly over about 90-120 min. During the addition, the temperature observed to be increased to 40-45°C and held constant. Then slowly raised the temperature to 60-65°C and maintained at this temperature for 3 hrs. After that, the reaction mass temperature maintained at 80-85°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%, MS (M+H): 212.23; IR (KBr, cm-1): 3500, 1720, 1360-1290; 1H-NMR (300 MHz, d, DMSO-d6) 12.8 (s, 2H), 8.2 (s, 3H); 13C-NMR (300 MHz, d, DMSO-d6): 164.1, 148.3, 135.2 133.4, 127.1.

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

A suitable reaction vessel was charged with 3500 mL of DM Water, 604.0 gm (7.75 mol) of sodium sulphide and mixed well. Then the vessel was charged 976.0 gm (11.65 mol) of sodium bicarbonate, followed by slow addition of 250.0 gm of 5-nitroisopthalic acid (2) (1.184 mol) about 30 minutes, in methanol. Slowly the reaction mass temperature was raised to 80-850C and stirred for about 5 hours. After completion of the reaction allowed to RT, filtered off, collected the aliquot and set the pH less than 2. Then it was stirred for 10 hour at 5-100C. The solid resulted was isolated by filtration, washed with DM water and dried. Yield: (204.0 gm) 95.0%, HPLC purity: 97.8%, MS (M+H) 182.5; IR (KBr, cm-1): 3500, 3020, 1715; 1H-NMR: (300 MHz, d, DMSO-d6) 13.1 (s, 2H), 8.2 (s, 3H), 6.23 (s, 2H); 13C-NMR (300 MHz, d, DMSO-d6); 167.4, 149.6, 134.3, 118.1, 117.4.

Example 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 5-aminoisopthalic acid (3) and mixed well. The temperature of the reaction mass was raised to 50-55°C, and then the reaction vessel was allowed by slow addition of 150.07 gm (5.89 mol) of NaICl2 solution in 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%, HPLC purity: 98.0 %, MS (M+H) 559.84; IR (KBr, cm-1): 3500, 3020; 1H-NMR: (300 MHz, d, DMSO-d6) 13.6 (s, 2H), 7.23 (s, 2H); 13C-NMR (300 MHz, d, DMSO-d6): 167.2, 139.2, 135.3, 97.3, 91.4.

Example 4: Synthesis of 5-aminotriiodo isophthaloyl dichloride (ATIPA-Cl) (5):

A suitable vessel was charged with 2500 mL of ethyl acetate, 250 gm (0.447 mol) of ATIPA (4), 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 36 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 sulphate, 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-ATIPA-Cl (5). Yield: (225.0 gm) 85.0 %, HPLC purity: 96.0%, MS (M+H): 596.9; IR (KBr, cm -1): 3500, 3020, 1725; 1H-NMR: (300 MHz, d, DMSO-d6), 7.38 (s, 2H); 13C-NMR (300 MHz, d, DMSO-d6) 165.3, 148.3, 136.3, 95.2, 86.2.

Example 5: Synthesis of (S)-1-((3, 5 bis (chlorocarbonyl)-2, 4, 6-triiodophenyl) amino-1-oxopropan-2-yl (7) :

A suitable vessel was charged with 500 mL of dimethyl acetamide (DMA), 250 gm (0.419 mol) of ATIPA-Cl (5) and mixed well. The reaction mass was allowed to cool at 0-5°C, followed by slow addition of 160.0 gm (1.049 mol) of 2-acetoxypropionyl chloride (6) at RT 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 chloroform (1500 mL) and washed by water. The organic layer was separated and washed by 2% aqueous sodium bicarbonate 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 (S)-1-((3, 5 bis (chlorocarbonyl)-2, 4, 6-triiodophenyl) amino-1-oxopropan-2-yl (7). Yield: (265.0gm) 90.0%, HPLC purity : 96.0 %, MS (M+H): 710.4; IR (KBr, cm-1): 3100, 3020, 1725, 1685; 1H-NMR: (300 MHz, d, DMSO-d6) 7.38 (s, 1H), 5.22 (q, 1H), 2.16 (s, 3H), 1.6 (d, 3H); 13C-NMR (300 MHz, d, DMSO-d6) 173.1, 172.3, 169.3, 147.3, 94.3, 83.4, 75.3, 26.4.

Example 6: Synthesis of (S)-1-((3, 5 bis ((1, 3-dihydroxypropan-2-yl) carbamoyl)-2, 4, 6-triiodophenyl) amino-1-oxopropan-2-yl acetate (9) :

A suitable vessel was charged with 250 mL of dimethyl acetamide (DMA), 250 gm (0.352 mol) of (S)-1-((3, 5 bis (chlorocarbonyl)-2, 4, 6-triiodophenyl) amino-1-oxopropan-2-yl (7) in 750 ml of acetonitrile and followed by addition of 143.4 gm (0.774 mol) of tributyl amine. The temperature of the reaction mass was raised to 45°C, and then 80.08 gm (0.88 mol) of serinol (8) in 250mL of DMA solution was added slowly to same vessel at same temperature about 120 minutes. Then temperature of the reaction mass was raised to 90°-100°C and stirred for about 5h. When the reaction was completed, reaction mass allowed to cool at RT and extracted by using DM water and dichloromethane, the aqueous layer was collected, treated by charcoal and filtered off on celite and distilled off to get desired compound (9). Yield: (200.0 gm) 72.0 % , HPLC purity : 92.0%, MS(M+H): 820.9; 1H-NMR: (300 MHz, d, DMSO-d6) : 8.3 (s 1H), 7.38 (s, 2H), 5.2 (s, 1H), 4.8 (m, 2H), 3.6 (d 8H), 2.1( s 3H), 1.89 (d, 3H); 13C-NMR (300 MHz, d, 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.

Example 7: Synthesis of Iopamidol (1):

A suitable vessel was charged with 1250 mL of methanol, 250.0 gm (0.305 mol) of (S)-1-((3, 5 bis ((1, 3-dihydroxypropan-2-yl) carbamoyl)-2, 4, 6-triiodophenyl) amino-1-oxopropan-2-yl acetate (serinol amide) (9) and mixed well. The reaction mass allowed to cool at 10-150C and charged 31.3 gm (0.781 mol) of sodium hydroxide to same vessel. The temperature of reaction mass was raised to 25 to 300C and stirred for about 120 minutes. Then the reaction vessel was added by charcoal and filtered off on celite bed. The collected aliquot was adjusted to pH 5 and cooled to 5-10°C followed by addition of silica-gel and stirred for about 2.0 h. The reaction mass was filtered off on celite bed, washed with water and collected the filtrate. Finally the aliquot was distilled out to get desired product of (S)-N1, N3-bis((1, 3-dihydroxypropan-2-yl)5(2-hydroxypropanamido)-2, 4, 6-triiodisophthalamide (1). Yield: (172.0 gm) 72.0%, HPLC purity : 99.0%, MS (M+H) : 778.4; 1H-NMR: (300 MHz, d, DMSO-d6) 8.6 (s 1H), 7.88 (s, 2H), 5.4 (s, 1H), 4.5 (m, 2H), 3.6 (d 8H), 2.1( s 3H), 1.69 (d, 3H); 13C-NMR (300 MHz, d, 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.

Purification of Iopamidol in DMA + Isopropyl alcohol:
A suitable vessel was charged with 250 mL of DMA at RT and 250.0 gm of Iopamidol (1), added to it and heated to 85°C and stirred for 3 hrs. Filtered the reaction mass at the same temperature through hyflow and washed with another 100 ml of DMA. The filtrate collected transferred in to another vessel and heated to 100°C and added slowly a 1550 ml of IPA at the same temperature. Maintain the reaction mass at 90°C for 6 hrs. Then colled the reaction mass to RT and stirred for 90 minutes. Filtered the thrown out compound and washed with another 250 ml of IPA. Then collected wet cake transferred in to another vessel and charged a premixed 5 volumes of Acetonitrile/IPA/Methanol, (1:1:1) and stirred for 1 hour at ambient temperature. Filtered the material and dried. HPLC purity: 99.34%, Yield: (222 gm) 88%, Chiral Purity: -4.62° in Water.

Purification of Iopamidol in Silica Gel:
A suitable vessel was charged with 1250 mL of DMA/water (1:1) at RT and 250.0 gm of Iopamidol (1), added to it and stirred for 3 hrs at 30-35°C. Then charged 65 gm of Silica gel (60-120) along with 5 ml of DMA and cooled to 5-7°C with stirring for 2 hrs. Filtered the reaction mass at the same temperature through hyflow and washed with another 250 ml of DM water. The filtered water distilled under vacuum at below 65°C with retaining a 10% of DM water left behind (25-30 ml). Then slowly add 1500 ml of ethanol by heating until reflux temperature reached. Stirred the reaction mass at the reflux of ethanol for 5 hrs and cooled to RT and filtered. The resultant solid was washed with another 125 ml of ethanol. The white wet cake obtained was dried under vacuum. HPLC purity: 99.67%., Yield: (222.2 gm) 88 %, Chiral Purity: -5.07° in Water.

Example 8: Synthesis of Iopamidol Crude (10):
A suitable vessel was charged with 200 L of DM Water, 200 L of 15% NH4OH, 100 kg of (S)-1-((3,5-bis((1,3-dihydroxypropan-2-yl)carbamoyl)-2,4,6-triiodophenyl)amino)-1-oxopropan -2-yl-acetate ((S)-Acetoxy Serinolamide 9) and mixed well. The temperature of the reaction mixture was kept at 40° to 45° C and stirred for about 4-6 hours. Then the reaction vessel was added activated charcoal and stirred for 1 to 2 hrs and filtered off on celite bed. The collected was distilled off completely to get desired product of 10. Yield: 85 kg (90.0%); HPLC Purity: 98.54% (RT 12.01 min); [a]D20 : -4.72° in 40% water; MS (M+H) : 778.4; 1H-NMR: (300 MHz, DMSO-d6) d 8.01 (1H), 7.90 (2H), 5.4 (1H), 4.6 (2H), 3.6 (8H), 3.2 (4H), 1.69 (3H); 13C-NMR (300 MHz, DMSO-d6) d 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.

Example 9: synthesis of (S)-1-(N-(3,5-bis((2,2-dimethyl-1,3-dioxan-5-yl)carbamoyl)-2,4,6-triiodophenyl) amino)-1-oxopropan-2-yl acetate (Compound-11)

A suitable vessel was charged with 450 L of Acetone, 28 L of 2,2-dimethoxy propane, 800 gm of p-TSA, 85 kg of compound (1) and mixed well. The temperature of reaction mass was kept at 45° to 50° C stirred for about 8 to 10 hrs. When the reaction completed, distilled off the solvent completely and slurred with hot water to get desired compound of 11. Yield: 81 kg (90.0%); HPLC Purity: 99.54%, (RT: 46.12 min); (M+H) 824; IR (KBr): 3300 cm¯1, 3020 cm¯1, 1685 cm¯1,1020 cm¯1; HI-NMR: (300 MHz, DMSO-d6) d 8.02 (1H), 7.92 (2H), 5.9 (1H), 4.86 (8H), 4.2 (2H), 2.1 (3H), 1.8 (15H); 13C-NMR (300 MHz, DMSO-d6) d 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.

Example 10: synthesis of Iopamidol (1)

A suitable vessel was charged with 81.0 L of DM Water, 81.0 L of hydrochloric acid, 81 kg of compound (11), and 8.5 mL of Trifluoroacetic acid and mixed well. The temperature of the reaction mass was kept 60° to 65°C and stirred for about 1 to 2 hrs. When the reaction completed, allowed the reaction mass to at RT and washed with 15 L of DCM/Chloroform. The reaction mass pH adjusted to neutral with ammonium hydroxide. Thus obtained aqueous layer was collected and completely distilled off. Thus obtained dissolved in 81 L of hot IPA to get desired product of 1. Yield: 68.3 kg (89.0 %); HPLC purity: 99.88% (RT 12.01); [a]D20: -5.09° in 40% water. MS (M+H) : 778.4; 1H-NMR: (300 MHz, DMSO-d6) d 8.01 (1H), 7.90 (2H), 5.4 (1H), 4.6 (2H), 3.6 (8H), 3.2 (4H), 1.69 (3H); 13C-NMR (300 MHz, DMSO-d6) d 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.

Example 11: synthesis of (S)-((5-(2-acetoxypropanamido)-2,4,6-triiodoisophthaloyl)bis(azanediyl))-bis- (propane-2,1,3-triyl) tetraacetate (11-A)

A suitable vessel was charged with 200 L of DMA and 85 kg of compound (1), 2.5 Kg of DMAP and mixed well and reaction mass cooled to 0° to 5° C. Then acetic anhydride 55.6 kg was slowly added to the cold reaction mixture during 1 to 2 hrs time. After the complete addition of acetic anhydride, the temperature of reaction mass was raised to RT and stirred for about 4 to 6 hrs. When the reaction completed, then slurred with hot water to get desired compound of 11-A. Yield: 97 kg (90.0%); HPLC Purity: 99.48%; (M+H) 988; IR (KBr): 3300 cm¯1, 3020 cm¯1, 1685 cm¯1, 1020 cm¯1; HI-NMR: (300 MHz, DMSO-d6) d 8.02(1H),7.92 (2H), 5.9 (1H), 4.86 (8H), 4.2 (2H), 2.1 (3H), 1.8 (15H); 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.

Example 12: synthesis of Iopamidol (1)

A suitable vessel was charged with 150 L of DM Water, 150 L of 15% NH4OH, 97 kg of compound (11-A) and mixed well. The temperature of reaction mass was raised to 40 to 450C and stirred for about 8 to 10 hours. Then the reaction vessel was charged with charcoal and filtered off on celite bed. The collected aliquot was distilled out completely to get desired product of 1. Yield: 66 kg, (89.0%); HPLC Purity: 99.82%; [a]D20: -4.92° in 40% water; MS (M+H) : 778.4; 1H-NMR: (300 MHz, d, DMSO-d6) 8.01 (1H), 7.90 (2H), 5.4 (1H), 4.6 (2H), 3.6 (8H), 3.2(4H), 1.69 (3H); 13C-NMR (300 MHz, d, 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.

Example 13: Comparison of yield, specific rotation and purification method with process of present invention over that of prior arts
The process of present invention provides the most optimum yield and specific rotation as compared to other processes of the prior art. The yield and specific rotation of the process of the present invention is compared with the theoretical and /or exemplified yield of prior art at table 1 for ready reference. The standard value of specific rotation lies in range of -4.6 to -5.2 as per USP. From the table 1, it can be seen that prior art either discloses good yield with no disclosure of specific rotation or low yield with standard specific rotation value.

Table 1
S. NO Prior art Yield (%) Specific Rotation ([a°]D) Purification method
1. US 4, 001, 323 65 -2.01 Exchange resin and recrystalization with alcohol
2. US 5, 550, 287 82.7, 86 Not given Strong and weak column, resin purification
3. US 6, 506, 938 96, 95, 96,97, 96.5, 97, 98.5, 80 Not given
4 US 7, 282,607/
48, 74 -4.5°, -5° Repeated solvent washing
5 US 2007/0078281
48, 74 -4.5°, -5° Column and resin purification
6 US 2005/0192465/
48, 74
-4.5°, -5° Column purificaton
7. US 5204005 Not given Not given Column purification
8. IP 2016/41010541 Silica gel and alcholhl mixture solvents
9. Present Invention 88 -5.07° Iopamidol crude prepared is acetylated of all the available OH groups in the molecule and penta acetyl iopamidol is highly soluble in organic solvents which facilitates to purify from so many structural analogue impurities. The subsequent deacetylation with NH4OH so that o-acetyl impurity will be comfortably eliminated.

The final purification is performed by recrystallization from Water and IPA to provide a very high pure Iopamidol with an SOR of -5.09° and purity of 99.82%.

From the table 1, it is clear that process of present invention provides very high yield, optimum specific rotation value and very high purity

Example 8: Comparison of yield and conditions in reduction for 5-nitro isopthalic acid to 5-amino isopthalic acid of present invention with prior arts
The prior art utilizes Pd/C and hydrogen for reduction of 5-nitro isopthalic acid to 5-amino isopthalic acid which provides low yield or product is not isolated. The comparisons of yield and reaction conditions for reduction are mentioned at table 2.

Table 2:
S. NO Prior art Yield (%) Conditions
1. US 4, 001, 323 Not isolated Pd/C, Hydrogen
2. US 5, 672, 735 Not isolated Pd/C, Hydrogen
3. US 6, 441, 235 66 Pd/C, Hydrogen
4. Present Invention 95 Na2S, Na2CO3

From the table 2, it is clear that when it utilizes Pd/C and hydrogen gas prior art does not provide a suitable yield for industrial scale up or in certain cases provides a very low yield which is not commercially viable. The advantageous use of sodium sulphide and sodium bicarbonate of the present invention results in high yield of 95%, which is suitable in scale up and is also commercially viable. ,CLAIMS:1. A process for the preparation of polyhydroxy compound of formula (1) and intermediates thereof

Comprising the steps of:
i. Selective nitration and subsequent reduction of isophthalic acid to obtain 5-amino isophthalic acid of formula (3) in presence of nitrating and reducing agent.

ii. Iodination of 5-amino isophthalic acid of formula (3) to obtain 5-amino-2,4,6-triiodoisophthalic acid of formula (4) by iodinating agent.

iii. Reacting 5-amino-2,4,6-triiodoisophthalic acid of formula (4) with thionyl chloride and phase transfer catalyst to obtain 5-ATIPA chloride of formula (5).

iv. Reacting 5-ATIPA chloride of formula (5) with 2-(S)-acetoxy propionyl chloride and dimethyl acetamide to obtain (S)-1-((3,5-bis(chlorocarbonyl)-2,4,6-triiodophenyl)) amino-1-oxopropan-2-yl of formula (7)

v. Reacting compound of formula (7) with 2-amino-1,3-dihydroxy propane in presence of organic base to obtain (S)-acetoxy serinolamide of formula (9)

vi. Hydrolysis of (S)-acetoxy serinolamide of formula (9) to obtain compound of formula (10) with demineralised water in presence of aqueous base;

vii. Protection of compound of formula (10) to obtain compound of formula (11) using ketone or to obtain compound of formula (11-A) using organic acid anhydride;

viii. Deprotection of compound of formula (11) with demineralised water in presence of acid to obtain polyhydroxy compound of formula (1) or deprotection of acetyl iopamidol (11-A) with demineralised water in presence of base/acid to obtain polyhydroxy compound of formula (1) and purification of polyhydroxy compound of formula (1) using DMA and organic solvents to obtain pure polyhydroxy compound of formula (1) provided that both deprotection and purification occur in a single step and no resins or no additional purification steps required.

(a) Optionally, hydrolysis of acetyl compound (9) in presence of aqueous base and silica gel to remove o- acetyl impurities to obtain crude polyhydroxy compound of formula (1).

(b) Purification of polyhydroxy compound of formula (1) with dimethyl acetamide and organic solvent to obtain pure polyhydroxy compound of formula (1) and final purification with silica gel and ethanol to obtain highly pure polyhydroxy compound 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 combination of HNO3with H2SO4, NaNO3 with H2SO4, KNO3 with H2SO4., preferably the nitrating agent is combination of HNO3 and H2SO4 p in a ratio of 0.1 to 3.5, more preferably 0.5 to 3.0, and most preferably 1.0 to 2.

3. The process as claimed in claim 1 wherein, the reducing agent used in step (i) may be selected from group comprising combination of sodium sulphide with NaHCO3, sodium bisulfate with NaHCO3, sodium thiosulphate with NaHCO3, sodium bis(2-methoxyethoxy)aluminium hydride with NaHCO3, sodium boro hydride with NaHCO3, sodium cyano borohydride with NaHCO3, sodium dithionite with NaHCO3, sodium hydrosulfite with NaHCO3, sodium hydroxyl methanesulfinate with NaHCO3, sodium tetrahydroborate with NaHCO3, sodium triacetoxy borohydride with NaHCO3, preferably the reducing agent is combination of sodium sulphide and NaHCO3 in a ratio of 0.1 to 3.0, more preferably 0.5 to 2.0 and most preferably 1.0 to 1.65.

4. The process as claimed in claim 1 wherein, the iodinating agent of step (ii) may be selected from group comprising I2 (molecular iodine), ICl (Iodine chloride), NIS (N-Iodo succinimide), NaCl2 (Sodium dichloroiodate), KICl2 (Pottasium dichloroiodate), more preferably NaCl2.

5. The process as claimed in claim 1 wherein, the phase transfer catalyst of step (iii) may preferably be selected from the ammonium bromide group comprising tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetramethyl ammonium bromide, trimethylvinyl ammonium bromide, tetrapropyl ammonium bromide, tetradecy ltrimethylammonium bromide, tetraamyl ammonium bromide, tetrahexyl ammonium bromide, tetraheptyl ammonium bromide, tetra-n-octyl ammonium bromide, trimethyl phenylammonium bromide, more preferably Tetrabutyl ammonium bromide.

6. The process as claimed in claim 1 wherein, the organic base of step (v) may be selected from the group comprising trimethyl amine, tributyl amine, triethyl amine, tripropyl amine, pyridine, piperidine more preferably tributyl amine.

7. The process as claimed in claim 1 wherein, the aqueous base used in step (vi) and step (viii) may be selected from group comprising sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, more preferably sodium hydroxide.

8. The process as claimed in claim 1 wherein, the organic solvent of step (viii) and step (ix)(b) may preferably be selected from the group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, tertiary butyl alcohol, acetone, ethyl acetate and the like or combination of above solvents, more preferably isopropyl alcohol.

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

10. The process as claimed in claim 1 wherein, the acid of step (viii) may be selected from the group comprising All mineral acids, Acetic Acid, p-TSA, trifluoro acetic acid or a combination thereof, preferably hydrochloric acid, trifluoro acetic acid or a combination thereof and base of step (viii) 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, step (iv) is carried out by reacting the compound of formula (5) with at least one mole of 2-(S)-acetoxy propionyl chloride.

12. The process as claimed in claim 1 wherein, step (v) is carried out by reacting the compound of formula (7) with at least two mole of 2-amino-1,3-dihydroxypropane.

13. The process as claimed in claim 1 wherein, the reaction of step (i) after completion of reduction is carried out maintaining the pH less than 4, more preferably less than 3, and most preferably less than 2.

14. The process as claimed in claim 1 wherein, the reaction of step (ix)(a) is carried out maintaining the pH less than 6, more preferably at 5.5 and most preferably at 5.5 to 6.0

15. A novel compound of formula (5), formula (7), formula (9), formula (10), formula (11) or (11-a)