FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
PROVISIONAL SPECIFICATION
A Process for Preparation of Hydralazine Hydrochloride
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400601, India
The following specification particularly describes the invention :

FIELD OF INVENTION
The present invention relates to a novel, cost-effective process for the preparation of an antihypertensive drug. Specifically, it relates to a process for the preparation of hydralazine hydrochloride.
BACKGROUND OF THE INVENTION
Hydralazine is a drug which is used to treat arterial hypertension, congestive heart failure, pulmonary hypertension in chronic obstructive pulmonary disease and aortic regurgitation. Recent observations indicate hydralazine can be used to withdraw patients from dobutamine in severe congestive heart failure and also it is useful for infants with chronic heart failure and left-to-right shunts. Hydralazine can also be used along with other drugs for treating and preventing mortality associated with heart failure, improving oxygen consumption, quality of life and/or exercise tolerance in a black patient with hypertension.
Hydralazine hydrochloride is an artery specific direct peripheral vasodilator drug used to treat essential hypertension and it is commercially available in both oral and injectable dosage forms in the U.S. and other countries. Despite approval by the U.S. Food and Drug Administration (FDA) for administration of 20 mg hydralazine hydrochloride injectable doses, several clinical hazards are reported with the currently available hydralazine injectable formulations. Stability of the sterile injection solution is a serious problem due to the formation of particles in the hydralazine sterile injection solutions during storage for more than six months. These stability issues with hydralazine hydrochloride injectable solutions are likely due to the minor impurities present in the drug.
The chemical name of hydralazine hydrochloride is 1-hydrazinophthalazine hydrochloride represented by formula I.


There are number of literatures available which describe the process for the preparation of compound of the formula (I). US patent 2484029 describes a process for preparing hydralazine from 1-chlorophthalazine. 1-chlorophthalazine is prepared from phthalazinone by the process reported in Ber. D. deutsch. chem. Ges., Vol., 26, page 521 (1893). Thus obtained moist chloro compound was further reacted with a mixture ethyl alcohol and hydrazine hydrate. The hydralazine thus obtained was recrystallized from methanol and converted to the hydrochloride salt on warming in alcoholic or aqueous hydrochloric acid. Hydralazine hydrochloride obtained by this process is found to contain several impurities at about 0.5%, has a greater than 0.01% level of hydrazine content, and does not comply with the present pharmacopoeial requirements for the drug. The starting material 1-chlorophthalazine prepared by this process is highly unstable during scale-up and leads to major insoluble in hydralazine stage.
US patent application 20050137397 discloses a process of preparing hydralazine hydrochloride involving the preparation of chlorophthalazine from phthalazinone and phosphorous oxychloride, separating using a first solvent such as an alkane having 5 to 7 carbons and a second solvent such as tetrahydrofuran, reacting the isolated chlorophthalazine with hydrazine in presence of alcohol to produce hydralazine, and treating the hydralazine with hydrochloric acid to yield hydralazine hydrochloride. The above reported process has a number of drawbacks. The chlorophthalazine prepared as disclosed in this application was found to contain more insoluble materials. In addition, the process of isolating chlorophthalazine, involves decanting a supernatant liquid mixture containing several volumes of hexane and phosphorous oxychloride, a cumbersome operation and that is a serious limitation towards scaling-up the disclosed process. Also hydralazine hydrochloride produced as described in this application is pale

yellow in color, and off-white after recrystallization from ethanol.
More recently, US7807830, discloses the process of preparing hydralazine hydrochloride by reacting phthalazinone with about one mole equivalent of phosphorus oxychloride and then acidifying the medium to produce a 1-chlorophthaiazine salt optionally in admixture with a mineral acid. Reacting the product of step (a) with hydrazine in an aqueous or alcoholic, and otherwise essentially non-organic, medium to produce hydralazine base and finally converting the hydralazine base to hydralazine hydrochloride. This process of isolation of 1-chlorophthalazine is not commercially viable since highly acidic salt isolation cannot be scaled up to industrial level.
US 7220858 describes a conventional process of preparation of 1-chlorophthalazine which involves heating a slurry of phthalazinone and phosphorus oxychloride to 70°C and then cooling to room temperature, concentrating the reaction mixture by heating at 45°C under vacuum. The resulting yellow paste was added toluene and further concentrated at 45 °C to remove phosphorus oxychloride/toluene azeotrope. The filtrate was basified by adding a base viz. sodium hydroxide into it. The resulting 1-chlorophthalazine is highly unstable and leads to disintegration to form many insoluble impurities. The process claimed as novel in this patent describes the preparation of 1-chlorophthalazine by heating phthalazinone and phosphorus oxychloride to 80°C. After completion of reaction the mixture was cooled to room temperature and hexane was added to it. The resulting slurry was stirred and hexane layer was decanted. This addition of hexane and decantation was repeated twice and THF was added to precipitate. The obtained solid was washed with cold THF to obtain off white 1-chlorophthalazine. This process is very cumbersome for industrial scale production.
The preparation of stable 1 -chlorophthalazine is very important in the process of preparation of Hydralazine hydrochloride because unstable 1-chlorophthalazine leads to formation of many insoluble impurities which hinders the production of acceptable quality of hydralazine hydrochloride required by many regulatory authorities.

Hydralazine hydrochloride is one of the drugs known for its instability in injectable solution during storage. This problem calls for the need of a process to produce hydralazine hydrochloride free of significant level of impurities The present inventors have developed a very cost effective and robust process for preparation of hydralazine hydrochloride which overcomes most of the above drawbacks.
SUMMARY OF THE INVENTION
The principal aspect of the present invention is to provide a process for the preparation of hydralazine hydrochloride of formula I, which comprises:
a) reacting phthalazinone of formula IV with an approximately equimolar equivalent of phosphorous oxychloride at a specific temperature to obtain a reaction mass;
b) basifying the obtained reaction mass by adding it slowly in aqueous ammonia and isolating 1-chlorophthalazine of formula III;
c) reacting the isolated 1-chlorophthalazine of formula III with hydrazine hydrate in presence of an organic solvent to form hydralazine base of formula II;
d) converting the hydralazine base of formula II to hydralazine hydrochloride of formula I in a aqueous medium and isolating therein; and
e) purifying the isolated hydralazine hydrochloride of formula I in aqueous hydrochloride.
The process of the present invention may be illustrated by the below reaction scheme:


DETAIL DESCRIPTION OF THE INVENTION
Accordingly in an embodiment of the invention, the reaction of phthalazinone of formula IV with phosphorous oxychloride is carried out at a temperature range of 50- 80 °C preferably at 55-65 °C for about 3 hours. After completion of reaction, the reaction mass was quenched preferably to pre cooled water and aqueous ammonia. The obtained reaction mixture is maintained at a pH in the range of 8.5-9.0. It has been observed that the conventional process add base into the reaction mixture of phthalazinone and phosphorous oxychloride, this leads to formation of highly unstable 1-chlorophthalazine, whereas addition of above reaction mixture into aqueous ammonia gives highly stable 1-chlorophthalazine. Thus obtained moist 1-chlorophthalazine is significantly stable and is free of chlorophosphorylphthalazine.
In another preferred embodiment of this invention, the reaction of 1-chlorophthalazine with an excess of hydrazine hydrate is carried out in presence of an organic solvent preferably an alcoholic solvent selected from methanol, ethanol, propanol and the like, more preferably methanol at the temperature range of 40 to 80° C preferably at 60-70 °C to obtain pure hydralazine base of formula II. After completion of the reaction the reaction mass was filtered hot to remove the insoluble and the hydralazine base was precipitated by cooling.

In yet another embodiment of the invention, the conversion of hydralazine base into hydralazine hydrochloride of formula I is carried out by heating hydralazine base with 15% hydrochloric acid at a temperature range of 60-90 °C, preferably at 70-80 °C. After completion of reaction, the obtained hydralazine hydrochloride precipitated by adding methanol.
In still another embodiment of the invention, the purification of the crude hydralazine hydrochloride may be carried out by any conventional process or by dissolving the crude hydralazine hydrochloride in 1% HC1.
Some of the noteworthy advantages of the process of the present invention are as given below:
a. The isolation of 1-chlorophthalazine at high pH by adding the reaction
mass of phthalazinone and phosphorous oxychloride into aqueous
ammonia gives highly stable 1-chlorophthalazine free of
chlorophosphorylphthalazine and other insoluble impurities. Whereas the
conventional process basifies in reverse order which leads to highly
unstable 1-chlorophthalazine having many insoluble impurities and yield
loss.
b. In the present invention the amount of phosphorous oxychloride used is
less than 1 mole equivalent to phthalazinone, which provides low
exothermicity and therefore a safer process, especially when scaled-up is
needed, whereas the prior art process suggests the use of phosphorous
oxychloride at much higher level of about 4 mole equivalent which
generates high exotherm.
The present invention is illustrated by the following examples, which are not to limit the scope of the invention.
Example: a) Preparation of 1-chlorophthalazine:

Phthalazinone (250 g) and phosphorus oxychloride (617 g) were charged into a 3 litre 3-necked flask fitted with a temperature probe and condenser. The slurry was stirred and heated to 50° C, maintained for 60 minutes. The mixture was allowed to cool to room temperature and quenched to a mixture of 15 volume of pre-cooled DM water and 7 vol. aqueous ammonia below 15°C. The above reaction mass attain a pH 8.5-9.0 at a temperature below 15° C. The obtained yellow solid was isolated by filtration and washed with cold DM Water to afford 1 -chlorophthalazine. Yield: 450-480g (wet) having 35-40% moisture
b) Preparation of Hydralazine:
Methanol (1000 ml) and hydrazine hydrate (885 ml) were charged into 2 litre 3-necked round-bottomed flask fitted with a temperature probe and condenser and the solution was cooled to 10° C. Wet 1-chlorophthalazine (500 g) was added in portions to maintain the solution temperature below 20 °C, stirred and heated to 60-70 °C. After one hour, hot solution was filtered to remove any insoluble by products and filtrate was cooled to 0-5 °C. A light yellow solid formed was isolated by filtration, washed with cold methanol and dried. Yield: 210-220 g
c) Preparation of Hydralazine Hydrochloride:
Hydralazine free base (25 g) and 15% hydrochloric acid (165 ml) were heated to a temperature of 70-80° C. Methanol (160 ml) was added to the above reaction mass, cooled to 25° C and further cooled to 3-8° C. A pale yellow precipitate of hydralazine hydrochloride was filtered and washed with chilled methanol. Yield: 26 g
d) Purification of Hydralazine Hydrochloride:
Hydralazine hydrochloride and 1% hydrochloric acid were charged into a single necked, round-bottom flask, heated to dissolve and filtered hot. Ethanol was added to the filtered hot solution, cooled to form an off-white precipitate of

purified hydralazine hydrochloride. The recrystallized, purified product was filtered and washed with cold ethanol.
Yield: 23 g Purity: 99.98%