CLIAMS:We Claim:
1. An improved process for the manufacture of Idarubicin hydrochloride of formula I

Formula I,
comprising:
(a) coupling (+)-4-demethoxy-daunomycinone of formula II

Formula II
with 6-halo-2-methyl-4-[(trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl trifluoro acetate of formula-IIIa

Formula IIIa,
in the presence of silver triflouromethylsulphonate, to obtain a mixture of unreacted compound of Formula II, mono-protected intermediate of Formula IVa and bis-protected intermediate of Formula IVe,
(b) saponifying the resultant mixture with a suitable inorganic base to obtain a mixture of unreacted compound of Formula II and Idarubicin free base,
(c) acidifying the resultant mixture with aqueous HCl to obtain an aqueous solution of idarubicin hydrochloride, and
(d) basifying the said aqueous solution and extracting the liberated pure idarubicin freebase Ia into an organic solvent, and
(e) treating the organic layer containing the free base Ia with methanolic hydrochloric acid solution to obtain idarubicin hydrochloride of Formula I.

2. The process as claimed in claim 1, wherein saponifying step is carried out by an aqueous solution of a suitable inorganic base sodium bicarbonate, sodium carbonate, potassium hydroxide or sodium hydroxide.

3. The process as claimed in claim 1, wherein any unreacted (+)-4-demethoxy-daunomycinone of formula II is recovered in substantially pure form and converted into idarubicin hydrochloride of formula I by the process of claim 1.

4. The process as claimed in claim 1, wherein X in formula IIIa is chlorine, bromine, fluorine or iodine.

5. The process as claimed in claim 1, wherein the coupling reaction is performed in the presence of molecular sieves.

6. The process as claimed in claim 1, wherein the reaction is performed in a single or binary mixture of ethereal or non ethereal organic solvent.

7. The process as claimed in claim 1, wherein the ethereal solvent is selected from diisopropyl ether, diethyl ether, tertiary butyl methyl ether, tetrahydrofuran or dioxane.

8. The process as claimed in claim 1, wherein the non-ethereal solvent is selected from dichloromethane, dichloroethane, dimethylformamide or dimethylsulphoxide.

9. The process as claimed in claim 1, wherein the reaction is performed at temperature ranging from -10ºC to 35ºC.

10. The process as claimed in claim 1, wherein the idarubicin hydrochloride (I) so obtained is NLT (not less than) 99.80% pure.

11. The process as claimed in claim 1, wherein the idarubicin hydrochloride (I) so obtained has NMT (not more than) 0.025% of the unconverted (II).
,TagSPECI:FIELD OF THE INVENTION

The present invention relates to an improved and scalable process for the preparation of substantially pure Idarubicin hydrochloride starting from (+)-4-demethoxy daunorubicinone, a useful anti-cancer chemotherapeutic drug. In particular, this invention relates to a process wherein Idarubicin hydrochloride is obtained in a substantially pure form and reasonable yield.

BACKGROUND OF THE INVENTION
Idarubicin hydrochloride chemically known as (1S,3S)-3-acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl-3-amino-2,3,6-trideoxo-a-L-lyxo-hexopyranoside hydro chloride is represented by the following structural formula I.

I

Idarubicin hydrochloride marketed under the trade names Zavedos in UK and Idamycin in USA by Pharmacia Upjohn is a DNA-intercalating analog of daunorubicin which has an inhibitory effect on nucleic acid synthesis and interacts with the enzyme topoisomerase II. The absence of a methoxy group at position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an increased rate of cellular uptake compared with other anthracyclines. The primary active metabolite formed is idarubicinol.

The first synthesis of Idarubicin hydrochloride has been disclosed DE 2525633; eidem US 4046878 (1976, 1977 both to Soc. Farmac. Ital.) now expired. The disclosed process as represented in scheme 01, comprises of condensing (+) demethoxy daunorubicinone (II) with 2,3,6-trideoxy-3-trifluoroacetamido-4-O-triflouroacetyl-a-L-lyxo-pyranosyl chloride (III) in an anhydrous solvent in the presence of mercuric oxide and / or mercuric bromide and molecular sieves. The reaction is stirred for 16 hours at room temperature. The said reaction provides a mixture of a-anomers (IVa) and (IVb) as represented in Scheme 01, along with their respective ß-anomers. The a-anomers (IVa) and (IVb) are then separated as a mixture from their respective ß-anomers by silica gel column chromatography, saponified and converted to hydrochloride salt.

The problem features, albeit of essential significance of the disclosed process, are described below.
Firstly, the disclosed process though starting from chirally pure 4-demethoxy daunorubicinone (II) leads to the formation of a mixture of a & ß-anomers which are separated by a tedious silica gel column chromatography method. Secondly, the process also does not teach about the isolation of pure Idarubicin hydrochloride (I) that is it does not provide a method for separating Idarubicin hydrochloride (I) from its (7R,9R)-a-glycoside (V) co-produced during its preparation.

Further the demonstration of the process as mentioned in this prior art is on 0.3g scale rendering lot of scope for improvement for providing a reasonably scalable process. Also the yield of the mixture (I) & (V) so obtained as mentioned is ~56% (w/w) which indirectly implicates a lower yield of pure idarubicin hydrochloride (I). As Idarubicin hydrochloride (I) obtained by the process is always contaminated with its ß-anomer (7R,9R)-a-glycoside (V) the optical purity of the so produced product is not guaranteed.
Also as the process provides mixture of isomer the process may not be commensurate with commercial manufacturing.

Scheme 01

Another US patent 4077988 describes an alternative process which is a total synthesis of optically active anthracyclinones (II) and isomers. It also exemplifies the synthesis of Idarubicin hydrochloride (I) as per the Scheme 02.

Scheme 02

The disclosed process comprises of the coupling of (+)-4-demethoxy daunorubicinone (II) with 1,2,3,6-tetradeoxy-4-O-triflouroacetylacetamido-L-lyxo-hex-1-enepyranose (VI) in the presence of p-toluenesulphonic acid in refluxing benzene to provide a mixture of N-protected a-glycoside (IVa) and ß-glycoside (IVc). Both the isomers are separated via silica gel column chromatography and converted individually to their respective hydrochlorides wherein the (7S,9S)-a-glycoside (IVa) provides idarubicin hydrochloride (I).

The drawbacks as evident from the disclosed process are as follows:
Firstly, the process employs benzene as a solvent which now has gained an extinct status in terms of its usage in process chemistry due its toxicity and other environmental factors, thus rendering the process not competitive enough for scale up. Secondly, the coupling reaction provides a mixture of a-glycoside (IVa) and ß-glycoside (IVc), which are separated via silica gel column chromatography thus limiting the scalability of the disclosed process.

Another prior art US Patent 4107423 describes a process as represented in Scheme 03. The process as disclosed employs racemic 4-demethoxy daunorubicinone (IIa) as the starting material which is coupled with 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-a-L-lyxo-pyranosyl chloride (III) in ether-dichloromethane mixture in the presence of silver trifuoromethanesulphonate to provide a mixture of (7S,9S)-a-glycoside (IVa) and ß-anomer (7R,9R)-ß-glycoside (IVd). The two isomers (IVa) and (IVd) are then separated by silica gel column chromatography, saponified and converted to idarubicin hydrochloride (I) and (VII) respectively. Thus this disclosed process as apparent also suffers with the associated drawbacks of silica gel column chromatography employed in one of the processing steps. Further the disclosed process is exemplified on 1g scale with ~35% (w/w) yield which is not sufficient to demonstrate the scalability of the disclosed process.

Scheme 03

Another prior art publication J. Chem. Soc. Perkin Trans. I 1982, pp 2249-2255 by Michael J. Broadhurst et.al, disclose a three step procedure for the preparation of idarubicin hydrochloride (I) of the desired optical purity. The disclosed process as represented in Scheme 04 involves coupling of (+)-demethoxy daunorubicinone (II) with 1-chloro-4-O-p-nitrobenzoyl-3-N-trifluoroacetyldaunosamine (VI) in the presence of silver triflate in a mixture of ether and tetrahydrofuran. The said reaction as disclosed claims to form the desired protected intermediate (VII) which is purified via chromatography on a column of silica gel. This purified intermediate (VII) is then treated in a mixture of dichloromethane-methanol mixture with 0.1N sodium hydroxide solution to remove the O-para-nitrobenzoyl protecting group to provide crude N-protected intermediate (IVa) which is obtained in pure form after silica gel column chromatography followed by trituration with diethyl ether. This pure N-protected (7S,9S)-a-glycoside (IVa) is then saponified and converted into idarubicin hydrochloride (I) by treatment of the free base with 0.1 N methanolic hydrochloric acid.

Scheme 04
The disclosed prior art process as apparent process suffers from the following drawbacks:
Firstly, the disclosed process utilizes the desired sugar molecule (VII) having two different protecting groups hence requiring additional deprotection step as evident from the represented scheme 04 to finally arrive at the desired product. Secondly, the process employs invariably silica gel column chromatography in combination of trituration with solvent to isolate intermediates of the process in pure form thus making the process equipment intensive and cumbersome. Also the process as disclosed has been demonstrated on milligram scale hence apprehending the reproducibility and scalability of the process.

Publications Chemistry Letters, pp. 501-504, 1984; Chemistry Letters, pp. 2113-2116, 1984 and Bulletin Chem. Soc. Jpn., Vol. 59, 423-431 (1986) by Kimura et. al. disclose a three step process, refer scheme 05, wherein (+)-demethoxy daunorubicinone (II) is reacted with 1,4-bis-O-(p)-nitrobenzyloyl-3-N-trifluoroacetyl daunosamine (VIII) in presence of Trimethylsilyl trifluorosulphonate at -40ºC in a mixture of ether and
Scheme 05
dichloromethane. The said reaction as disclosed forms the desired protected intermediate (VII) which is purified via chromatography on a column of silica gel. This purified intermediate (VII) is then treated in a mixture of dichloromethane-methanol mixture with 0.1N sodium hydroxide solution to deprotect the O-para-nitrobenzoyl group to provide crude N-protected intermediate (IVa) which is again purified by silica gel column chromatography. This pure N-protected (7S,9S)-a-glycoside (IVa) is then saponified and converted to idarubicin hydrochloride (I) by treatment of the free base with 0.1N methanolic hydrochloric acid.

This summarized general process of the various publications by Kimura et. al. in our view have the following short comings:
Firstly, the process employs an intermediate (VIII) which have different protecting groups for Nitrogen and Oxygen of the sugar molecule which require additional deprotection steps as the case is. Also the synthesis of the said intermediate (VIII) would invariably employ costly reagent viz., p-nitrobenzoyl chloride or anhydride making the process uneconomical. Secondly, the use of trimethylsilyl triflate a costly coupling agent which also enforces the requirement of a low temperature -40ºC for its use in the coupling step is an additional drawback and hindrance to scale up. Further the coupling product (VII) so produced is subjected to column chromatography which carries its own associated drawbacks in terms of scalability of the process.

Apart from the above summarized prior art and their associated drawbacks invariably none of the prior arts mention about the following critical attributes
a. The presence of unconverted demethoxy daunorubicinone (II) or (IIa) during the coupling reaction and hence its fate during the process, which as observed at our end is present invariably in all the employed coupling methodologies.
b. The chemical purity of the obtained idarubicin hydrochloride (I).

Thus it is evident from the prior art that a need for a scalable, operationally and economically viable process for the preparation of substantially pure idarubicin hydrochloride (I) persists.

SUMMARY OF THE INVENTION
The aim of the present invention is to provide an improved, scalable and economical procedure for the preparation of idarubicin hydrochloride (I) in substantially pure form.

In one aspect, the present invention provides an improved process for the manufacture of Idarubicin hydrochloride of formula I

Formula I
The said process comprises the steps of:
(a) coupling (+)-4-demethoxy-daunomycinone of formula II

Formula II
with 6-halo-2-methyl-4-[(trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl trifluoro acetate of formula-IIIa

Formula IIIa,
in the presence of silver triflouromethylsulphonate, and
(b) saponifying the resultant coupled N-protected idarubicin solution in situ with an aqueous solution of sodium hydroxide to obtain Idarubicin hydrochloride of formula I.

In one specific embodiment, the present invention provides an improved process for the manufacture of Idarubicin hydrochloride of formula I

Formula I,
wherein the process comprises the steps of:
(a) coupling (+)-4-demethoxy-daunomycinone of formula II

Formula II
with 6-halo-2-methyl-4-[(trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl trifluoro acetate of formula-IIIa

Formula IIIa,
in the presence of silver triflouromethylsulphonate, to obtain a mixture of unreacted compound of Formula II, mono-protected intermediate of Formula IVa and bis-protected intermediate of Formula IVe,
(b) saponifying the resultant mixture with a suitable inorganic base to obtain a mixture of unreacted compound of Formula II and Idarubicin free base,
(c) acidifying the resultant mixture with aqueous HCl to obtain an aqueous solution of idarubicin hydrochloride,
(d) basifying the said aqueous solution and extracting the liberated pure idarubicin freebase Ia into an organic solvent, and
(e) treating the organic layer containing the free base Ia with methanolic hydrochloric acid solution to obtain idarubicin hydrochloride of Formula I.

In another aspect, the present invention also provides a process for the manufacture of Idarubicin hydrochloride of formula I, wherein any unreacted (+)-4-demethoxy-daunomycinone of formula II is recovered in substantially pure form and converted into idarubicin hydrochloride of formula I by the process of the present invention.

In yet another aspect, the X in formula IIIa is chlorine, bromine, fluorine or iodine. In a preferred embodiment, X is chlorine.

In yet another aspect, the present invention provides a process for the manufacture of Idarubicin hydrochloride of formula I, wherein the coupling reaction is performed in the presence of molecular sieves.

In another aspect, the present invention provides a process for the manufacture of Idarubicin hydrochloride of formula I, wherein the reaction is performed in a single or binary mixture of ethereal or non-ethereal organic solvent.

In one embodiment, the ethereal solvent is selected from diisopropyl ether, diethyl ether, tertiary butyl methyl ether, tetrahydrofuran or dioxane. In a preferred embodiment, the ethereal solvent is diethyl ether.

In another embodiment, the non-ethereal solvent is selected from dichloromethane, dichloroethane, dimethylformamide or dimethylsulphoxide. In a preferred embodiment, the non-ethereal solvent is dichloromethane.

In one aspect, the present invention provides a process for the manufacture of Idarubicin hydrochloride of formula I, wherein the reaction is performed at a temperature ranging from -10ºC to 35ºC.

In another aspect, present invention provides a process for the manufacture of Idarubicin hydrochloride of formula I, wherein the idarubicin hydrochloride (I) so obtained is NLT (not less than) 99.80% pure.

In yet another aspect, the present invention provides a process for the manufacture of Idarubicin hydrochloride of formula I, wherein the idarubicin hydrochloride (I) so obtained has NMT (not more than) 0.025% of the unconverted (II).

The objectives as mentioned above will be apparent in the following detailed description.

DETAILED DESCRIPTION OF THE PROCESS
While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

Definition:
For the purposes of this invention, the following terms will have the meaning as specified therein:

Saponification/Saponifying: Basic hydrolysis of an amide or ester group of a molecule.
Basification: pH adjustment using aqueous solution of an inorganic base.

The process of the present invention is illustrated in scheme 06 as described below.

Scheme 06
The present invention provides an improved, scalable and economical procedure for the preparation of substantially pure idarubicin hydrochloride which comprises of,
(1) reacting (+)-4-demethoxy daunorubicinone (II) with a suitable N,O-bis-trifluoroacetyl-1-halo daunosamine derivative (IIIa)

Formula IIIa

in the presence of silver trifluoromethane sulphonate in a suitable single or mixture of ethereal or non ethereal organic solvents at a suitable temperature to give a solution containing mixture of unreacted II, mono-protected intermediate IVa and bis-protected intermediate IVe, saponifying this mixture with aqueous sodium hydroxide to get a mixture of idarubicin free base Ib and unreacted II, separating unreacted II after acidification with aqueous HCl and obtaining idarubicin hydrochloride I as an aqueous solution from which (1S,3S)-3-acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl-3-amino-2,3,6-trideoxo-a-L-lyxo-hexopyranoside hydrochloride or Idarubicin hydrochloride (I) is isolated after basification with aqueous sodium hydroxide, dichlormethane extraction and treatment with methanolic HCl, and

(2) recovering the unreacted (+)-4-demethoxy daunorubicinone (II) and converting it to substantially pure idarubicin hydrochloride (I) following step (1).

The present invention further provides a process wherein the glycosidic coupling of (II) and (IIIa) is performed preferably in the presence of molecular sieves.

The present invention further provides a process wherein halogen atom X in sugar derivative IIIa used for coupling is Chlorine, Bromine, Fluorine or Iodine, more preferably Chlorine.

The present invention further provides a process wherein 1.5 to 2.2 molar equivalent of sugar derivative IIIa is used for coupling.

The present invention further provides a process wherein the suitable ethereal solvent for the glycosidation reaction is chosen from diisopropyl ether, diethyl ether, tertiary butyl methyl ether, tetrahydrofuran or dioxane.

The present invention further provides a process wherein the suitable non-ethereal solvent is chosen from dichloromethane, dichloroethane, dimethylformamide or dimethylsulphoxide.

The present invention further provides a process wherein 120 to 400 volume of the chosen single or mixture of ethereal or non-ethereal solvents is used for the glycosidation reaction.

The present invention further provides a process wherein the reaction is performed at temperature ranging from -10ºC to 35ºC.

The present invention further provides a process wherein the unreacted (+)-4-demethoxy daunorubicinone (II) is recovered in substantially pure form and resubjected to the best reaction (glycosidation) conditions of the present invention to furnish additional substantially pure idarubicin hydrochloride (I) thus increasing the overall efficiency of idarubicin hydrochloride (I) preparation.

The present invention further provides a process wherein idarubicin hydrochloride (I) is produced in a yield of 75 to 85% (w/w).

The present invention provides a process wherein the produced idarubicin hydrochloride (I) is NLT (not less than) 99.8% pure.

The present invention further provides a process wherein produced idarubicin hydrochloride is contaminated with NMT (not more than) 0.05% of the unreacted (+)-4-demethoxy daunorubicinone (II).

Thus the present invention provides an improved scalable and economical procedure for the preparation of substantially pure idarubicin hydrochloride (I) which not only overcomes the problems as encountered in practicing the prior art methods but also provides solution to the unanswered fate of unconverted intermediate (II) in terms of its recovery and recyclability in being again converted into idarubicin hydrochloride (I) thus improving the over all yield of idarubicin hydrochloride (I) without compromising on its quality. The process of the present invention avoids completely the use of tedious silica gel column chromatography thus making the process scalable to commercial scale.

The following examples illustrate, but in no way limit the scopes of the novel process of this invention. Any deviation from this, apparent and obvious to a person skilled in the art of organic synthesis, forms part of this invention though not explicitly substantiated.

Example 1
Preparation of Idarubicin hydrochloride (I):
Charged under nitrogen dichloromethane (2640ml) followed by (+)-4-demethoxy daunomycinone (II) (20.0g) stirred at 25-30ºC till clear solution was obtained. Then the reaction mixture was cooled to 5-10ºC and stir for 10 minutes. Then a solution of N,O-bistrifluoroacetyl-1-chloro-daunosamine (III) (36.8g) in dichloromethane (376ml) followed by previously dried molecular sieves (80.0g) was charged into the reaction mixture at 5-10ºC and the reaction mass was stirred at 5-10ºC for 10 minutes. Then a solution of silver triflate (37g) in diethyl ether (2640ml) was added and the reaction mixture was allowed to come to 23-25ºC under stirring for 1 h. The reaction mixture was then filtered through celite bed which was washed with dichloromethane (1000ml). The collected Dichloromethane filtrate was then washed three times with 1% aqueous sodium thiosulphate (3 X 1120ml) at 23-25ºC. The dichloromethane layer was then cooled to 3-5ºC and treated with sodium hydroxide (0.3N, 1000ml) for 40-45 minutes after which methanol (400ml) and process water (2400ml) was charged and reaction mixture allowed to come to 23-25oC. The pH of the resultant biphasic mixture was then adjusted to ~5.5 using aqueous hydrochloric acid (1N) at 23-25oC. The upper aqueous layer containing Idarubicin hydrochloride (I) was separated from the lower dichloromethane layer containing un-reacted (+)-4-demethoxy daunomycinone. The pH of the aqueous layer was adjusted to ~7.5 using 0.2N ammonium hydroxide solution at 23-25oC after which it was extracted five times with dichloromethane (5 X 1280ml). The combined dichloromethane layer was then concentrated at 30ºC under vacuum till ~700ml volume. The obtained concentrated mass was then cooled to 0-5ºC after which a mixture of 2N methanolic .HCl (16ml) and dichloromethane (160ml) was added and the contents stirred at the same temperature for 15 minutes. The precipitated solid was then filtered, washed with dichloromethane (720ml), pet ether (300ml), suck dried the solid for 2-3hrs under vacuum and finally dried under vacuum at 50oC for 24 hrs.
Weight of solid: - 12.5g, Yield: 62.3% (w/w)
HPLC purity: 99.87%, Int (II): 0.01%; Assay: 98.24 % (OAB); SOR: +205O (c = 0.1 in methanol)

Example 2
Recovery of (+)-4-demethoxy daunomycinone (II):
Concentrated the organic layer from Example 1 completely under vacuum at 40oC wherein 8.6g of crude 4-demethoxy daunomycinone was obtained (HPLC purity 74%). This crude solid was refluxed in a mixture of dichloromethane (43ml) and methanol (43ml) for 2 hours. The reaction mass was then cooled to 20ºC after which the precipitated solid was filtered, washed with 1:1 mixture of dichloromethane: Methanol (17.2ml), suck dried and dried the solid under vacuum at 40oC for 24 hrs.
Dry wt: 6g.
Purity by HPLC: 98.67.
Example 3
Preparation of idarubicin hydrochloride (I) from recovered (+)-4-demethoxy daunomycinone (II)
(II) as recovered in Example 2 was subjected to coupling reaction as per the procedure of Example 1.
Weight of solid: - 3.5g, Yield: 58.3% (w/w)
HPLC purity: 99.90%, Int. (II): BDL (Below detection limit); Assay: 98.9 % (OAB); SOR: +206O (c = 0.1 in methanol)
Overall yield of (I): Output of Example 4 + Output of Example 6 = 16g [80% w/w].

We Claim:
1. An improved process for the manufacture of Idarubicin hydrochloride of formula I

Formula I,
comprising:
(a) coupling (+)-4-demethoxy-daunomycinone of formula II

Formula II
with 6-halo-2-methyl-4-[(trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl trifluoro acetate of formula-IIIa

Formula IIIa,
in the presence of silver triflouromethylsulphonate, to obtain a mixture of unreacted compound of Formula II, mono-protected intermediate of Formula IVa and bis-protected intermediate of Formula IVe,
(b) saponifying the resultant mixture with a suitable inorganic base to obtain a mixture of unreacted compound of Formula II and Idarubicin free base,
(c) acidifying the resultant mixture with aqueous HCl to obtain an aqueous solution of idarubicin hydrochloride, and
(d) basifying the said aqueous solution and extracting the liberated pure idarubicin freebase Ia into an organic solvent, and
(e) treating the organic layer containing the free base Ia with methanolic hydrochloric acid solution to obtain idarubicin hydrochloride of Formula I.

2. The process as claimed in claim 1, wherein saponifying step is carried out by an aqueous solution of a suitable inorganic base sodium bicarbonate, sodium carbonate, potassium hydroxide or sodium hydroxide.

3. The process as claimed in claim 1, wherein any unreacted (+)-4-demethoxy-daunomycinone of formula II is recovered in substantially pure form and converted into idarubicin hydrochloride of formula I by the process of claim 1.

4. The process as claimed in claim 1, wherein X in formula IIIa is chlorine, bromine, fluorine or iodine.

5. The process as claimed in claim 1, wherein the coupling reaction is performed in the presence of molecular sieves.

6. The process as claimed in claim 1, wherein the reaction is performed in a single or binary mixture of ethereal or non ethereal organic solvent.

7. The process as claimed in claim 1, wherein the ethereal solvent is selected from diisopropyl ether, diethyl ether, tertiary butyl methyl ether, tetrahydrofuran or dioxane.

8. The process as claimed in claim 1, wherein the non-ethereal solvent is selected from dichloromethane, dichloroethane, dimethylformamide or dimethylsulphoxide.

9. The process as claimed in claim 1, wherein the reaction is performed at temperature ranging from -10ºC to 35ºC.

10. The process as claimed in claim 1, wherein the idarubicin hydrochloride (I) so obtained is NLT (not less than) 99.80% pure.

11. The process as claimed in claim 1, wherein the idarubicin hydrochloride (I) so obtained has NMT (not more than) 0.025% of the unconverted (II).

IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE IDARUBICIN HYDROCHLORIDE

Abstract
The present invention relates to an improved scalable and economical process for the preparation of substantially pure Idarubicin hydrochloride, a useful anti-cancer chemotherapeutic drug. In particular, this invention relates to a process wherein Idarubicin hydrochloride is obtained in a substantially pure form and with reasonable yield.