FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules,2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF PYRAZOLONE DERIVATIVES OF
HIGH PURITY''
2. APPLICANT (S):
(a) NAME: BDR Pharmaceuticals International pvt. Ltd.,
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS:'407-408 Sharda chambers, New Marine Lines, Mumbai - 400020,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention:
The present invention relates to an improved and industrially adoptable process for the synthesis of Pyrazolone derivatives of formula (I), having high purity.

Background and Prior Art:
Pyrazolone derivatives of structure (I) have been shown to have antioxidant as well as antiulcer activity.( JP Patent Publication ( Kokai) No 5-293159 A ( 1993). Amongst them, Edaravone (IA) having chemical name 3-Methyl-l-Phenyl-2-Pyrazolin-5-one, R2 =CH3, Rl = H, R3 = Ph, is a compound recognized to have potential effectiveness as antioxidant It is commercially available as an injection preparation under the name of Radicut (Mitsubishi Pharma). Pyrazolone derivatives of structure (I) have been found to be effective in the treatment of cerebrovascular disorders, such as cerebral stroke, brain tumor, cerebral ischemia etc. The product is administrated as intravenous injection.
It is observed that Pyrazolone derivatives are unstable in nature. For example, Edaravone as such has very less stability in liquid solutions whereas it has comparatively better stability as a solid. During the synthesis, many impurities are formed as byproducts and they are carried further in the product during product isolation in various proportion. The quality of the injection preparation is always dependent on the purity of Edaravone solid. The purity of Edravone has to be monitored by carefully monitoring the synthesis process and eliminating the byproducts during the synthesis itself.

Therefore, there is a need to obtain a commercially adoptable process wherein the desired Pyrazolone derivatives can be synthesized in high purity and yields.
The inventors of the present invention have successfully determined the strategy of systematic elimination of impurities at various stages to yield Pyrazolone of having desired level of purity and very low level or absence of many known/unknown and undesired impurities.
Disclosure of the invention:
The synthesis of Pyrazolone derivatives of formula (I) having different substituents with high purity have been prepared by developing a strategy of selective removal of impurities during the synthesis.

wherein, Rl, R2, R3 are same or different, Rl, R2, R3 constitute hydrogen, hydroxyl, nitro, amino, substituted amino, sulphonyl or substituted sulphonyl, boronyl or substituted boronyl, siliconyl or substituted siliconyl, alkyl, branched alkyl, unsaturated alkyl, halo alkyl, nitro alkyl, amino alkyl, sulfo alkyl, aryl, substituted aryl, hetero alkyl or heteroaryl.
The compounds of formula (I) can exist in base, salts, solvates, hydrates, free form or in acid addition salt form, etc.
The synthesis comprises of reacting a Hydrazine compound in the form of base or it's acid addition salt of following formula (II)
R3-NH-NH2.Hx.

(II)
Wherein, R3 is having substituents as described above and Hx is organic or inorganic acid salt, with a keto-ester of following formula (III), in suitable solvents like aliphatic alcohols, aromatic hydrocarbons, halogenated aliphatic and aromatic solvents, ethers, esters, alkoxy-aliphatic solvents, etc.

Wherein Rl= hydrogen or C1 to C3 lower alkyl; R2= methyl, ethyl; R4= methyl or ethyl.
The reaction can be carried out from temperature ranging from about 20 degree to the boiling point of the solvents. The stochiometric molar ratio proportion of the hydrazine compound (II) to the Keto-ester (III) can be from 1:0.5 to 1: 100 moles, specifically from 1:1.5 moles, more specifically from 1:0.8 moles. The time period of the reaction ranges from about 1 hr to 32 hours.
The reaction is generally carried out at atmospheric pressure and optionally under applied or external pressure conditions.
The progress of the reaction is monitored by usual techniques known to the art of synthesis such as using TLC or HPLC and after completion of the reaction, the solvent is distilled under reduced pressure. The reaction mass is then extracted with suitable solvent (Solvent I or the first solvent) to remove undesired impurities. The extraction can be undertaken either in presence or in absence of water. The product rich organic layer is then worked up and the solvent is distilled under reduced pressure. To the reaction mass which is in the form of residue, another solvent (solvent II or the second solvent) is added to selectively dissolve the impurities and the product crystallizes out in a substantially pure form.
If required, the product thus obtained is recrystallized further from a suitable solvent (solvent III or third solvent), to obtain Pyrazolone derivative (I) in pure form.

The first solvent may be selected from chlorinated hydrocarbons such as chloroform and dichloromethane. The second solvent may be selected from hydrocarbons such as cyclohexane and hexane and the third solvent may be selected from alcohols such as ethanol and isopropanol.
The present invention thus offers an improved and convenient process for the synthesis of Pyrazolone derivatives in a pure form, which can be easily scaled-up to commercial scale. The present invention exemplifies one such example to prepare edaravone of formula I, wherein, R2 =CH3, Rl = H, R3 = Ph, in good yield with high purity.
The following preparative examples are given by way of illustration only and not to be construed as limiting the scope of invention.
Example 1
In a suitable glass reaction assembly, 600 ml of Ethyl alcohol and 100 gm of Phenyl Hydrazine followed by 100 ml of Ethylacetoacetate is charged. The mass was then refluxed for 8 hours. The solvent was distilled under reduced pressure and to the reaction mass was added 250 ml water followed by 200 ml Chloroform (Solvent I), it was stirred and allowed to settle. The organic layer was separated and the aqueous layer was extracted with 2 X 100 ml Chloroform. The combined organic phase was further washed with water and then with saturated Sodium Chloride solution. The organic phase was then dried over Sodium Sulphate. The solvent was then distilled under reduced pressure to obtain a residue. To this residue, was then added with 200 ml Cyclohexane (Solvent II) and heated under reflux for 15 minutes. The reaction mass was cooled to room temperature and then chilled to 15 degree for 1 hr. The slurry was then filtered and washed with 50 ml of chilled Cyclohexane. The solid thus obtained was dried under vacuum to yield 75 gm of Edaravone purity by HPLC 98 to 99%.

Crystallization:
75 gm of the product is dissolved in ethanol (Solvent III) and heated to obtain a clear solution. To the same was added activated charcoal and heated under stirring for 30 min. followed by filtration. The clear filtrate was then cooled and stirred for 2 hrs at 10° C. The crystals thus obtained were filtered, washed with chilled ethanol and the product dried under vacuum to obtain Edaravone 52 gm, HPLC purity 99.6%.
Example 2
In a suitable glass reaction assembly, 600 ml of Ethyl alcohol and 100 gm of Phenyl Hydrazine HC1 followed by 105 ml of Ethylacetoacetate is charged. The mass was then refluxed for 8 hours. The solvent was distilled under reduced pressure and to the reaction mass was added 300 ml water followed by 200 ml Chloroform (Solvent I), and it was stirred and allowed to settle. The organic layer was separated and the aqueous layer was extracted with 2 X 100 ml Chloroform. The combined organic phase was further washed with water and then with saturated Sodium Chloride solution. The organic phase was then dried over Sodium Sulphate. The solvent was then distilled under reduced pressure to obtain residue. To this residue, was then added with 200 ml Cyclohexane (Solvent II) and heated under reflux for 15 minutes. The reaction mass was cooled to room temperature and then chilled to 15 degree for 1 hr. The slurry was then filtered and washed with 50 ml of chilled Cyclohexane. The solid thus obtained was dried under vacuum to yield 76 gm of Edaravone purity by HPLC 98 to 99%.
Crystallization:
75 gm of the product was dissolved in ethanol (Solvent III) and heated to obtain a clear solution. To the same was added activated charcoal and heated under stirring for 30 min. followed by filtration. The clear filtrate was then cooled and stirred for 2 hrs at 10° C. The crystals thus obtained werre filtered, washed with chilled ethanol and the product dried under vacuum to obtain Edaravone 51 gm, HPLC purity 99.7%.

Example 3
In a suitable glass reaction assembly, 1200 ml of Isopropyl alcohol and 200 gm of Phenyl Hydrazine HC1 followed by 225 ml of Ethylacetoacetate was charged. The mass was then refluxed for 8 hours. The solvent was distilled under reduced pressure and to the reaction mass was added 900 ml water followed by 300 ml Dichloromethane (Solvent 1), and it was stirred and allowed to settle. The organic layer was separated and the aqueous layer was extracted with 2 X 300 ml Dichloromethane. The combined organic phase was further washed with water and then with saturated Sodium Chloride solution. The organic phase was then dried over Sodium Sulphate. The solvent was then distilled under reduced pressure to obtain residue. To this residue, was then added with 400 ml hexane (Solvent II) and heated under reflux for 15 minutes. The reaction mass was cooled to room temperature and then chilled to 15 degree for 1 hr. The slurry was then filtered and washed with 100 ml of chilled hexane. The solid thus obtained was dried under vacuum to yield 158 gm of Edaravone , purity by HPLC 98 to 99%.
Crystallization:
150 gm of the product was dissolved in isopropanol (Solvent III) and heated to obtain a clear solution. To the same was added activated charcoal and heated under stirring for 30 min. followed by filtration. The clear filtrate was then cooled and stirred for 2 hrs at 10° C. The crystals thus obtained were filtered, washed with chilled isopropanol and the product dried under vacuum to obtain Edaravone 105 gm, HPLC purity 99.82%.

We claim,
1. A process for preparation of Pyrazolone derivatives of formula (I) or its pharmaceutical salt or hydrate comprising;

wherein, Rl, R2, R3 are same or different, Rl, R2, R3 constitute hydrogen, hydroxyl, nitro, amino, substituted amino, sulphonyl or substituted sulphonyl, boronyl or substituted boronyl, siliconyl or substituted siliconyl, alkyl, branched alkyl, unsaturated alkyl, halo alkyl, nitro alkyl, amino alkyl, sulfo alkyl, aryl, substituted aryl, hetero alkyl or heteroaryl
a) reacting hydrazine compound in the form of base or it's acid addition salt of
formula II
R3-NH-NH2.Hx.
(II) wherein R3 is having substituents as described above and Hx is organic or
inorganic acid salt,
b) with a keto-ester of following formula (III),


wherein R1 = hydrogen or C1 to C3 lower alkyl; R2= methyl or ethyl; R4= methyl or ethyl.
in suitable solvents selected from the group consisting of aliphatic alcohols, aromatic hydrocarbons, halogenated aliphatic and aromatic solvents, ethers, esters and alkoxy-aliphatic solvents; and
c) isolating the compound of formula I from the reaction mass by distilling the solvent under reduced pressure.
2. The process according to claim 1, wherein said reaction is carried at a temperature of 20°C to the boiling point of the solvents..
3. The process according to claim 1, wherein, the stoichiometric molar ratio of the hydrazine compound (II) to the Keto-ester (III) is from 1:0.5 to 1: 100 moles.
4. The process according to claim 1, wherein, the stoichiometric molar ratio of the hydrazine compound (II) to the Keto-ester (III) is 1:1.5 moles.
5. The process according to claim 1, wherein, the stoichiometric molar ratio of the hydrazine compound (II) to the Keto-ester (III) is 1: 0.8 moles.
6. The process according to claim 1, wherein, said isolation process of pyrazolone derivative of formula 1 further comprising:

a) extracting the reaction mass with first solvent to remove undesired impurities;
b) distilling the first solvent to obtain product rich organic layer;
c) adding second solvent to crystallize out the product in a substantially pure form by selectively dissolving the impurities; and
d) optionally crystallizing the product obtained in the above step from third solvent.

7. The process according to claim 6, wherein, said first solvent is selected from chlorinated hydrocarbons such as chloroform and dichloromethane.
8. The process according to claim 6, wherein said second solvent is selected from hydrocarbons such as cyclohexane and hexane.
9. The process according to claim 6, wherein said third solvent is selected from alcohols such as ethanol and isopropanol.

10.The process according to any one of the preceding claims, wherein said Pyrazolone derivatives of formula (I) is edaravone, wherein, R2 =CH3, R1 = H, R3 = Ph.