The present invention relates to an industrially feasible and.cost effective process for the preparation of pure Hydrochlorothiazide of formula I.
ON yO ON ,0 H2N" >^^< ^NH

(formula I)
BACKGROUND OF THE INVENTION
The chemical name of Hydrochlorothiazide is 6-Chloro-3, 4-dihydro-2H-l, 2, 4-benzothiadiazine-7-sulfonamide-l, 1-dioxide and formula is C7H8CIN3O4S2 and molecular weight is 297.73 g/mol.
Hydrochlorothiazide is used as diuretic. It is generally used in combination with antihypertensive drugs such as Irbesartan, Valsartan, Candesartan Cilexetil, Olmesartan, Telmisartan, Catopril, Enalapril, Fosinopril, Lisinopril, Quinapril, Moexipril, Benazepril, Propranolol, Metoprolol Tartarate, Bisoprolol, Methyldopa and Hydralazine. It is also used in combination with other diuretic drugs such as Amiloride and Triamterene. Hydrochlorothiazide is used to treat high blood pressure and fluid retention caused by various conditions, including heart disease.
US patent no. 3,163,645 discloses process for the preparation of Hydrochlorothiazide, which involves reacting 5-chloro-2, 4-disulfamyl-aniline or its salt with aldehyde such as formaldehyde in the absence or presence of a base and a solvent. The base is alkali metal hydroxide and the solvent is selected from THF, dioxane, diethylene glycol, methanol and water or mixtures thereof.

In other method, 5-chloro-2, 4-disulfamyl-aniline is reacted with paraformaldehyde in the presence of a mineral acid and a solvent. Preferably, the aldehyde is reacted with the aniline derivative in about stoichiometric amounts. The reaction may be performed in the absence of any condensing agent, or in the.presence of a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, whereby the aldehyde is used in its reactive form. The reaction may also be carried out in the presence of a small amount of an acid, particularly a mineral acid, such as hydrohalic acid, e.g. hydrochloric or hydrobromic acid, or sulfuric acid. Thus, for example, when formaldehyde is used as the reactant, it may be desirable to use it in the form of a polymer, such as paraformaldehyde or trioxane, or as an acetal, such as dimethoxymethane or diethoxymethane. Hydrochlorothiazide obtained is recrystallized from water. However, the overall yield obtained by this process is only 46%, which makes the process less attractive for industrial scale. Moreover repeating this experiment, it is found that it results in the formation of dimer impurity of formula C (2-3%) along with Hydrochlorothiazide which is very difficult to remove by conventional purification methods.

This patent also discloses a preparation of an alkali metal salt of Hydrochlorothiazide, a process for converting it to a free compound by treating it with mineral acid and then converting the free compound to an alkali metal salt. But this patent does not disclose any purification process involving acid^ase treatment.

US patent no. 3,227,710 discloses a process for the preparation of Hydrochlorothiazide which involves reacting 4,6-dichloro-benzene-l,3-disulfonic acid dichloride with 30% aq. formaldehyde in the presence of saturated alcoholic ammonia solution at 150°C for 10 hrs. The solvent is distilled off and residue obtained is acidified with dil. HC1. The oily reaction product crystallizes on standing in a refrigerator. The product is further charcoalized in 60% ethanol and then recrystallized from the same solvent. This patent discloses purification by crystallization and charcoalization methods but is silent on the purity and yield.
US patent no. 3,267,095 discloses a process for the preparation of Hydrochlorothiazide which involves reacting 5-chloro-aniline 2,4-disulfonyl chloride with paraformaldehyde in the presence of HC1 gas in diethyleneglycol diethylether to give an intermediate which is further reacted with an anhydrous ammonia to give solid product which is further purified by recrystallization from aqueous methanol to give Hydrochlorothiazide. This patent is silent about the purity and yield.
The content of undesired impurity in the final product is always a cause of concern with respect to Food and Drug Authorities (FDA) requirement. Therefore, it is required to have the undesired impurity content well below the level specified in the International Conference on Harmonization (ICH) guidelines as per regulatory authority. Particularly with respect to the known impurity the acceptable limit is 0.15%. Therefore it is extremely important to control the level of dimer impurity of formula C, to comply with the regulatory requirement.
The known processes suffer from the drawbacks such as (a) longer reaction period such as 10 hr (b) low yield (c) use of combination of bases like NaOH and ammonia, (d) Use of solvents like ethanol or diethylene glycol dimethyl ether (e) higher reaction temperature such as about 150°C and (f) formation of dimer impurity make the prior-art processes less productive and infeasible at industrial scale.

In view of the preparation methods available for Hydrochlorothiazide, there is a need for simple, industrially feasible having mild reaction conditions, cost effective and environmental friendly process for the preparation of Hydrochlorothiazide that is free from one or more of the above mentioned drawbacks and achieves good yield and purity.
The problem has been solved by the applicant by providing an improved process, which allows a convenient and efficient synthesis of Hydrochlorothiazide by a process which also ensures the formation of dimer impurity to a level less than 0.10%.
To overcome the disadvantages of the state of the art, the present invention provides a process for the synthesis of Hydrochlorothiazide by reacting 4-amino-6-chlorobenzene-1,3-disulfonamide of formula II with formaldehyde in the absence of an acid or base in water at 95°C-100°C to yield crude Hydrochlorothiazide of formula III which upon purification gives pure Hydrochlorothiazide of formula I.
The present inventors observed that when 4-amino-6-chlorobenzene-l, 3-disulfonamide is reacted with paraformaldehyde in the presence of acid or base, dimer impurity is generated in the reaction along with the formation of Hydrochlorothiazide, which is difficult to remove by conventional purification method. The present inventors reacted 4-amino-6-chlorobenzene-1, 3-disulfonamide with paraformaldehyde in the absence of any acid or base and surprisingly found that the generation of dimer impurity is very low. The present inventors also directed their research work towards developing a purification process in which dimer impurity is removed. Surprisingly, a novel process for purification of crude Hydrochlorothiazide was found in which the said impurities are considerably reduced to comply the regulatory needs. The present inventors also found that the Hydrochlorothiazide obtained by process of present invention followed, by the purification is having purity of at least 99.5% and dimer impurity to a level less than 0.10%.
OBJECT OF THE INVENTION

It is a principal object of the present invention to improve upon one or more limitations from the prior arts by providing an improved process for the preparation of Hydrochlorothiazide.
It is another object of the present invention to provide a simple, commercially viable, economical and environment friendly process for preparing Hydrochlorothiazide, in good yield and purity.
It is still another object of the present invention to provide pure Hydrochlorothiazide having dimer content less than 0.10%.
SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided an improved and industrially feasible process for the manufacture of pure Hydrochlorothiazide of formula I, as shown in scheme 1.
Scheme: 1

°v° °v°
H2N"YY NH2
A^
CI
NH-

Paraformaldehyde
DM Water 95-100°C

owo owo
H2N v ^ ' NH
x &> -J
CI N H

l.Aq.NH3/Conc.HCl
2. DM Water

H2N

CI

YV NH
N H

4-amino-6-chlorobenzene-l,3-disulfonamide
(formula II)

Crude
Hydrochlorothiazide
(formula III)

Pure
Hydrochlorothiazide
(formula I)

It has been unexpectedly found that pure Hydrochlorothiazide of formula I is efficiently prepared from process as shown in scheme 1.
DESCRIPTION OF THE INVENTION
6

The present invention {scheme 1) relates to an improved process for the preparation of Hydrochlorothiazide comprising the steps of, reacting 4-amino-6-chlorobenzene-l,3-disulfonamide of formula II with formaldehyde in the absence of an acid or base in water at 95-100°C to yield crude Hydrochlorothiazide of formula III which upon purification gives pure Hydrochlorothiazide of formula I.
According to the present invention formaldehyde can be used in a form of polymer such as paraformaldehyde or trioxane or as an acetal, such as dimethoxymethane or diethoxymethane. In a preferred embodiment paraformaldehyde is used as formaldehyde.
The dimer content in pure Hydrochlorothiazide prepared by above method is less than 0.15%. Preferably, the dimer content in pure Hydrochlorothiazide prepared by above method is less than 0.10%.
According to the present invention, the reaction is carried out at temperatures sufficient to form Hydrochlorothiazide, preferably at 90°C-100°C and more preferably at 95°-100°C.
The advantage of the present invention can be easily understood by analyzing the data of purity and yield depicted in the following table:

Prior art method (using mineral acid) Present invention method
(in water, but in the absence of
acid or base)
Dimer content (%) 2.48 <0.10
Yield (%) 46 83.65
The present invention further provides a process for preparation of pure
Hydrochlorothiazide of formula I having purity of at least 99.5% comprising steps of:
(i) stirring crude Hydrochlorothiazide of formula III with a mixture of aq. Ammonia
solution and water;
(ii) adding an activated carbon;
(iii) adjusting pH to about 6 to 7 with mineral acid and
7

(iv) isolating pure Hydrochlorothiazide of formula I.
In the process of the present invention, the purification can be achieved by stirring crude Hydrochlorothiazide with a mixture of aq. ammonia and water. An activated charcoal/carbon is added to the reaction mixture, stirred well and filtered through hyflo bed. The pH of the filtrate is adjusted to about 6 to about 7, by adding mineral acid such as. dilute aq. hydrochloric acid. Then reaction mixture was stirred for 45-60 min. The resulting solid is filtered, washed with water and suck dried. The solid product is finally dried to give pure Hydrochlorothiazide of formula I.
According to the present invention, wherein said mineral acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid and the like or mixtures thereof.
According to the present invention, wherein said isolation is done preferably by filtration method.
The process for the preparation of Hydrochlorothiazide as described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples
Example 1: Preparation of Hydrochlorothiazide
4-Amino-6-chlorobenzene-l, 3-disulfonamide (50.0 g) was heated with paraformaldehyde (5.51 g) in water (750 ml) at reflux temperature for 2 to 3 hours. The reaction mixture was cooled to 25°C to 30°C and stirred for 2-3 hours. The precipitated solid was filtered and washed with water (50 ml x3) and suck dried. The product crude Hydrochlorothiazide is obtained as white wet cake which is taken for purification.
Example 2: Purification of Hydrochlorothiazide
8

Crude Hydrochlorothiazide wet cake obtained in Example 1 was charged in a mixture of aq. ammonia (150 ml) and water (100 ml). The reaction mixture was stirred for 10-15 min. at 25°C to 30°C. Activated carbon (2.5 g) was added and stirred for further 25-30 min. The reaction mixture was filtered through hyflo bed and washed with water. The pH of filtrate was adjusted to about 6 to about 7 by adding dilute aq. HC1 (320 ml). Resulting solid was filtered, washed with water (50 ml x2) and suck dried. The wet solid was charged with water (250 ml) and heated to 80°C to 85°C for 30-40 min. The reaction mixture was cooled to 25°C to 30°C, filtered the solid, washed with water (50 ml x2) and suck dried. The resulting solid was dried in hot-air oven at about 55°C to 60°C for 14 to 15 hours to give pure Hydrochlorothiazide as white crystalline solid (44.0 g). % Yield: 84.62% Purity (by HPLQ: 99.91% Dimer content: Below detection limit
LOD (Limit of detection): 0.01%
Example 3: Preparation of Hydrochlorothiazide
4-Amino-6-chlorobenzene-l,3-disulfonamide (100.Og) was heated with paraformaldehyde (11.02 g) in water (1500 ml) at reflux temperature for 2 to 3 hours. The reaction mixture was cooled to 25°C to 30°C and stirred for further 2-3 hours. The precipitated solid was filtered and washed with water (100 ml x3) and suck dried. The product crude Hydrochlorothiazide is obtained as white wet cake which is taken for purification.
Example 4: Purification of Hydrochlorothiazide
Crude Hydrochlorothiazide wet cake obtained in Example 3 was charged in a mixture of aq. ammonia (300 ml) and water (200 ml). The reaction mixture was stirred for 10-15 min. at 25°C to 30°C. Activated carbon (5.0 g) was added and stirred for further 25-30 min. The reaction mixture was filtered through hyflo bed and washed with water. The pH of filtrate was adjusted to about 6 to about 7 by adding dilute aq. HC1. Resulting solid was filtered, washed with water (100 ml x2) and suck dried. The wet solid was charged with water (500 ml) and heated to 80°C to 85°C for 30-40 min. The reaction mixture was cooled to 25°C

to 30°C and continued stirring for another 1 hour, filtered the solid, washed with water
(100 ml x2) and suck dried. The resulting solid was dried in hot-air oven at about 55°C to
60°C for 14 to 15 hours to give pure Hydrochlorothiazide as white crystalline solid (87.Og).
% Yield: 83.65%
Purity (by HPLQ: 99.93%
Dimer content: Below detection limit
LOD (Limit of detection). 0.01%

Claims:
A process for the preparation of Hydrochlorothiazide of formula I

cr v N H
(formula I)
comprising the steps of:
reacting 4-amino-6-chlorobenzene-l,3-disulfonamide of formula II

Cr v NH2 (formula D)
with formaldehyde in the absence of an acid or base in water to obtain Hydrochlorothiazide (I) having dimer impurity less than 0.10%.
The process as claimed in claim 1, wherein said formaldehyde is used in a form of polymer such as paraformaldehyde or trioxane or as an acetal such as dimethoxymethane or diethoxymethane or mixtures thereof.
The process as claimed in claim 1, wherein said formaldehyde is preferably paraformaldehyde.
A process for the preparation of Hydrochlorothiazide of formula I having purity of
at least 99.5% comprising steps of:
(i) stirring crude Hydrochlorothiazide of formula III

Os ,0 ON ,0

H2N

NH

cr ^ N
H (formula III)
with a mixture of aq. ammonia solution and water; (ii) adding an activated carbon;
(iii) adjusting pH to about 6 to 7 with mineral acid and (iv) isolating pure Hydrochlorothiazide of formula I.
The process as claimed in claim 4, wherein said mineral acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid or mixtures thereof
The process as claimed in claim 4, wherein said isolation is done preferably by filtration method.
A process for preparation pure Hydrochlorothiazide of formula I
H2N" jV NH
H (formula I)
having purity of at least 99.5% a and dimer content less than 0.10%
comprising steps of:
(i) reacting 4-amino-6-chlorobenzene-l;i3-disulfonamide of formula II

*»-
V"¥°

(formula II)
with formaldehyde in the absence of an acid or base in water to obtain crude Hydrochlorothiazide of formula III;
CX X> (X fO

(formula TO)
(ii) stirring crude Hydrochlorothiazide of formula III with a mixture of aq.
Ammonia solution and water;
(iii) adding an activated carbon;
(iv) adjusting pH to about 6 to 7 with mineral acid and
(v) isolating pure Hydrochlorothiazide of formula I.
The process as claimed in claim 7, wherein said formaldehyde is used in a form of polymer such as paraformaldehyde or trioxane or as an acetal such as dimethoxymethane or diethoxymethane or mixtures thereof
Hydrochlorothiazide prepared according to the process of claim 1, wherein dimer impurity of formula C


HoN

is less than 0.10%.
Hydrochlorothiazide prepared according to the process of claim 7, wherein dimer impurity of formula C