HYDROCHLORIDE MONOHYDRATE

FIELD OF THE INVENTION The present invention relates to an improved process for preparation of the Hydrochloride Monohydrate salt of 6,7-dichloro-l,5-dihydroimidazo (2,1-b) quinazolin-2(3H)-one, commonly known as Anagrelide Hydrochloride Monohydrate (la)

BACKGROUND OF THE INVENTION The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Anagrelide, chemically known as 6,7-dichloro-l,5-dihydroimidazo[2,l-l)]quinazolin-2(3H)-one Hydrochloride Monohydrate (formula la) is a potent blood platelet reducing agent.

Anagrelide was first disclosed in US3932407A (henceforth US'407), which discloses preparation of Anagrelide shown in below scheme- 1. US'407 describes the preparation of Anagrelide, wherein the condensation of (I) with ethyl glycinate (II) by means of triethylamine in refluxing ethanol gives ethyl N-(2-nitro-6- chlorobenzyl)glycinate (III), which is reduced with H2 over Pd/C in ethanol yielding ethyl N-(2- amino-6-chlorobenzyl)glycinate (IV). The cyclization of (IV) with cyanogen bromide (A) in refluxing ethanol affords 6-chloro-l,2,3,5-tetrahydroimidazo[2,l-b]quinazolin-2-one (V), which is finally chlorinated with CI2 and FeCh in hot nitromethane.

The Anagrelide Hydrochloride Monohydrate (formula la) was prepared for the first time in US patent number US5801245 (henceforth US'245) as shown in scheme-2, wherein the intermediate, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine (7) was reacted with cyanogen bromide in hot alcohol solution, or, preferentially, by reaction with cyanogen bromide in an aprotic solvent to give an iminoquinazoline intermediate (8) which was isolated and then reacted with a base in a hot solution of alcohol to form Anagrelide free-base (1). The hydrochloride monohydrate Anagrelide salt (la) was prepared by adding hydrochloric acid to a methanol slurry of Anagrelide free -base (1) and heating to reflux.

The process disclosed in US'245 leads to formation of methyl ester impurity (ring opening) in substantial amount formed by reaction of Anagrelide free -base with reactive alcoholic solvent in presence of acidic media.

It is therefore an object of the present invention to provide an improved process for the preparation of Anagrelide Hydrochloride Monohydrate (la).

It is also an aim of the present invention to provide a process, which minimizes the need for final purification. It is thus an aim to provide a route to prepare the compound of formula (la), which offers an improved yield relative to the existing routes. Still further objects and advantages of the present invention will become apparent from the details provided in the specification.

SUMMARY OF THE INVENTION

The problem addressed by the present invention is that of providing an improved, efficient, economic and an industrially viable process for preparation of Anagrelide Hydrochloride Monohydrate compound of formula (la).

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 illustrates X-ray powder diffraction (XRD) of form-P of Anagrelide hydrochloride monohydrate, prepared according to example 4.

Figure 2 illustrates X-ray powder diffraction (XRD) of form-R of Anagrelide hydrochloride monohydrate, prepared according to example 5.

Figure 3 illustrates X-ray powder diffraction (XRD) of form-M of Anagrelide hydrochloride monohydrate, prepared according to example 6.

Figure 4 illustrates X-ray powder diffraction (XRD) of form-L of Anagrelide hydrochloride monohydrate, prepared according to example 7.

DETAILED DESCRIPTION OF THE INVENTION

Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for describing the particular embodiments only, and is not intended to limit the scope of the present invention.

Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials described within but similar, equivalent to those described herein can be used in the practice, or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including, " "containing, " "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further, the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.

As used herein, the phrase "Ambient temperature" or room temperature” often abbreviated as “RT” means that the temperature at which the subject reaction mixture is maintained is close to, or the same as that of the space, e.g., the room or fume hood, in which the reaction is being carried out. Typically, room temperature is from about 20° C. to about 30° C., or about 22° C. to about 27° C., or about 25° C.

Accordingly, the present invention relates to an improved process for the preparation of Anagrelide Hydrochloride Monohydrate compound of formula (la), comprising;

(a) dissolving Anagrelide free-base in a solvent to form a solution;

(b) treating the step a) solution with a hydrochloric acid or alcoholic hydrochloric acid;

(c) optionally adding an anti-solvent to the step b) solution; and

(d) isolating the Anagrelide Hydrochloride Monohydrate compound of formula (la). Step (a) of the foregoing process involves the dissolution of Anagrelide free-base in a solvent, which is selected from Hexafluoroisopropanol (HFIPA), Trifluoroacetic acid (TFA) or Formic acid.

The alcoholic hydrochloric acid solution used in step (b) is prepared just by adding concentrated hydrochloric acid in alcohol solvent. The alcoholic solvent used for the same is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol or isobutanol.

The anti-solvent used in step (c) is an alcoholic solvent, which is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol or isobutanol.

The inventors of the present invention have found that after following the prior art process, which involves the preparation of Anagrelide hydrochloride salt formation by addition of aqueous hydrochloric acid in mixture of Anagrelide free-base and Methanol or Ethanol at reflux or ambient temp, leads to substantial formation of methyl or ethyl ester impurity (ring opening) by reaction of Anagrelide with reactive alcoholic solvent in presence of acidic media.

The stability of reaction media and methyl ester impurity formation at different temperatures are shown below in different tables A to E along with conclusion.

Table-A: Heating of Anagrelide free -base, aqueous HC1 in ethanol at 85° C (reflux) for the preparation of HC1 salt of Anagrelide.

Conclusion: Ring opening ethyl ester impurity generated during heating with ethanol in presence of acid getting increases during salt formation. Table-B: Heating of Anagrelide free-base, aqueous HC1 in Methanol at 65° C (reflux) to analyse formation of methyl ester impurity during preparation of HC1 salt of Anagrelide.

Conclusion: Ring opening methyl ester impurity is generated during heating with methanol in presence of acid during salt formation. Due to methyl ester impurity formation in higher amounts, the solid i.e. Anagrelide HCI does not precipitate or crystallize out even after cooling.

Table-C: Heating of Anagrelide HCI API in methanol at 65° C (reflux) to analyse impact of excess acid on methyl ester formation during Anagrelide HCI formation.

Conclusion: Ring opening methyl ester impurity is generated to lower extent during heating of API with methanol in absence of acid. Higher temperature in the presence of acid and presence of methanol solvent enhances the excess methyl ester formation.

Table-D: Heating of Anagrelide free-base with aqueous HCI in Methanol at 50° C to analyse formation of methyl ester impurity during Anagrelide HCI formation. I 10 h | 71.4 | 25.7 I

Conclusion: Ring opening methyl ester impurity is formed and continues to increase over a period of digestion at 50° C in presence of acid during salt formation.

Table-E: Stirring of Anagrelide free-base with aqueous HC1 in Methanol at 25-30° C to analyse formation of methyl ester impurity during Anagrelide HC1 formation.

Conclusion: Ring opening methyl ester impurity is formed and continues to increase during the course of a reaction at ambient condition in presence of acid during salt formation.

Therefore, in view of the aforementioned problems associated with the prior art process related to ring opening impurity formation (methyl ester impurity), the inventors of the present invention have employed Hexafluoroisopropanol or Trifluroacetic acid or formic acid solvent for the dissolution of Anagrelide free -base and formation of Anagrelide hydrochloride salt in methanol- HC1 solution. On scale up, desired polymorph is achieved by stirring the Anagrelide hydrochloride monohydrate in hydrochloric acid solution. While carrying out the present invention the stability of reaction mass for the formation of methyl ester impurity is monitored during Anagrelide hydrochloride monohydrate formation. The obtained results are tabulated below in Table F.

Table-F: Stirring of Anagrelide free-base with aqueous HC1 in Hexafluoroisopropanol at 40° C to analyse formation of methyl ester impurity during for salt formation.

Conclusion: Negligible methyl ester impurity as well as no other impurity shows during 12 h stirring of Anagrelide free -base with aqueous HC1 in Hexafluoroisopropanol at 40° C during Anagrelide HC1 salt formation.

Table-G: Stirring of Anagrelide free -base with aqueous HC1 in Hexafluoroisopropanol and methanol at 25-30° C to analyse formation of methyl ester impurity during for salt formation.

Conclusion: Anagrelide HC1 is highly soluble in HFIP. The product was isolated by methanol solvent addition at ambient temperature. The solution shows stability and methyl ester impurity was controlled to below 1% after stirring for a period of 10 hours.

Advantages of lower rate of ring opening methyl ester impurity formation:

❖ yield improved to 80% as against 50-60% by using only methanol as reaction solvent as reported in prior art process thereby making the process more cost effective;

❖ robustness on operation point of view, scale up, less degradation, efficient process and overall quality improvement.

❖ process developed is capable of purging USP related impurities along with any other impurities. Therefore, no purification is required during final isolation and desired polymorph of Anagrelide was isolated directly from Mixture of HFIP and methanol with purity of >99.9%.

❖ lower volumes of methanol required as compared to that in the prior art process.

❖ process developed can be operated at ambient temperature. According to yet another embodiment, the present invention provides a novel crystalline form herein designated as form-P of Anagrelide hydrochloride monohydrate. Figure 1 illustrates X- ray powder diffraction (XRD) of form-P of Anagrelide hydrochloride monohydrate, prepared according to example 4.

According to the present invention, the process of preparation of form-P of Anagrelide hydrochloride monohydrate comprises: a) dissolving Anagrelide hydrochloride monohydrate (1.0 equivalent) in HFIPA (5.0 volume) at 25-35°C; b) preparing a solid film at -20°C of clear solution obtained in step (a); c) lyophilizing the solid film obtained in step (b) for 18 hours to get a form-P of Anagrelide hydrochloride monohydrate.

According to yet another embodiment, the present invention provides a novel crystalline form herein designated as form-R of Anagrelide hydrochloride monohydrate. Figure 2 illustrates X- ray powder diffraction (XRD) of form-R of Anagrelide hydrochloride monohydrate, prepared according to example 5.

According to the present invention, the process of preparation of form-R of Anagrelide hydrochloride monohydrate comprises: a) dissolving Anagrelide hydrochloride monohydrate (1.0 equivalent) in TFA (5.0 volume) at 35-40°C; b) preparing a solid film at -20°C of clear solution obtained in step (a); c) lyophilized the solid film obtained in step (b) for 18 hours to get form-R of Anagrelide hydrochloride monohydrate.

According to yet another embodiment, the present invention provides a novel crystalline form herein designated as form-M of Anagrelide hydrochloride monohydrate. Figure 3 illustrates X- ray powder diffraction (XRD) of form-M of Anagrelide hydrochloride monohydrate, prepared according to example 6. According to the present invention, the process of preparation of form-M of Anagrelide hydrochloride monohydrate comprises: a) dissolving Anagrelide hydrochloride monohydrate (1.0 equivalent) in HFIPA (5.0 volume) at 25-35°C; b) distilled out the solvent on rotary evaporator at 25-35°C to get form-M of Anagrelide hydrochloride monohydrate.

According to yet another embodiment, the present invention provides a novel crystalline form herein designated as form-L of Anagrelide hydrochloride monohydrate. Figure 4 illustrates X- ray powder diffraction (XRD) of form-L of Anagrelide hydrochloride monohydrate, prepared according to example 7.

According to the present invention, the process of preparation of form-L of Anagrelide hydrochloride monohydrate comprises: a) dissolving Anagrelide hydrochloride monohydrate (1.0 equivalent) in TFA (5.0 volume) at 35-40°C; b) distilled out the solvent on rotary evaporator at 35-40°C to get form-L of Anagrelide hydrochloride monohydrate.

EXAMPLES

Example 1

Preparation of Anagrelide hydrochloride monohydrate by using Hexafluoro isopropanol (HFIPA)

In a 250 mL capacity four-necked reactor equipped with a mechanical stirrer, thermo-pocket (TP), stopper and condenser. 40.0 mL of Hexafluoroisopropanol (HFIPA) and 10.0 g Anagrelide free- base at 25-35°C were charged. The reaction mixture was heated to 40-45° C followed by 8.0 mL of concentrated HC1 added and was maintained for 10-20 min. The hot reaction mass of temperature 40-45°C was filtered through desired micron filter and washed with 10.0 mL Hexafluoroisopropanol. The filtrate was charged into a clean and dry 250 mL capacity four-necked reactor equipped with a mechanical stirrer, thermo-pocket (TP), stopper and condenser. The reaction mixture was heated to 40-45° C followed by drop wise addition of methanol Lot-1 over a period of ~ 30 minutes and maintained ~ 1 h. The reaction mass was cooled to 0-10°C and maintained for 2-3 h. Solid obtained was filtered under vacuum at 0-10°C and washed with 10.0 mL methanol Lot-2. Wet solid obtained was dried under vacuum at 25-35°C for 12 h to provide Anagrelide hydrochloride monohydrate.

Result:

Theoretical Yield : 1.21

Practical Yield : 50-100 g

Yield (%) : 42-83 %

Yield (w/w) : 0.50 - 1.00

In a 250 mL capacity four-necked reactor equipped with a mechanical stirrer, thermo-pocket (TP), stopper and condenser. 20.0 mL of Trifluoroacetic acid (TFA) and 5.0 g Anagrelide free-base at 25-35°C were charged and stirred for 10-20 mins. To this reaction mixture, methanolic HC1 solution (4.0 ml cone. HC1 in 100.0 ml methanol lot-I) was added below 30°C temperature and the reaction mixture was stirred for 1 h at 25-35°C and again for 2-3 hr at 0-10°C. Solid obtained was filtered under vacuum at 0-10°C and washed with 10.0 mL methanol lot-2. Wet solid obtained was dried under vacuum at 25-35°C for 12 h to provide Anagrelide hydrochloride monohydrate.

Result:

Theoretical Yield : 1.21

Practical Yield : 50-100 g

Yield (%) : 42-83 %

Yield (w/w) : 0.50 - 1.00

Example 3

Preparation of Anagrelide hydrochloride monohydrate by using Formic acid:

Anagrelide free-base (1 equivalent) was dissolved in formic acid (2.5 volumes) at 30-35°C, which was then filtered through micron filter and was rinsed with formic acid (0.5 V). To this reaction mixture, methanolic HC1 solution (0.8 volumes of cone. HC1 in 20 volumes of methanol) was added dropwise and stirred for 1-1.5 h at 25-35°C. The reaction mass was cooled to 0-10 °C and stirred for 2-3 h. Solid obtained was filtered and washed with (2 volumes) of methanol. If IPC-1 (In-Process Control) met the desired limit, the wet cake was charged with 25% aq. HC1 solution (2.5 volumes) for 5-6 h at 25-35°C. If IPC-2 met the desired limit for IR correlation coefficient, then solution was filtered and the wet cake was dried under vacuum for 12 h at 25-35°C. If IPC-3 met the desired limit for moisture content and residual solvents, the material was packed in mentioned packaging and stored at recommended conditions.

Result:

Theoretical Yield : 1.21

Yield (%) : 56-82 %

Yield (w/w) : 0.68 - 1.00

Example 4

Preparation of form-P of Anagrelide hydrochloride monohydrate

Anagrelide hydrochloride monohydrate (1.0 equivalent) was dissolved in HFIPA (5.0 volumes) at 25-35°C to get clear solution. This obtained clear solution was made into thin solid film at -20°C. This solid film was subjected to lyophilization for 18 h to obtain form-P of Anagrelide hydrochloride monohydrate.

Example 5

Preparation of form-R of Anagrelide hydrochloride monohydrate

Anagrelide hydrochloride monohydrate (1.0 equivalent) was dissolved in TFA (5.0 volumes) at 35-40°C to get clear solution. This obtained clear solution was made into thin solid film at -20°C. This solid film was subjected to lyophilization for 18 h to obtain form-R of Anagrelide hydrochloride monohydrate.

Example 6 Preparation of form-M of Anagrelide hydrochloride monohydrate

Anagrelide hydrochloride monohydrate (1.0 equivalent) was dissolved in HFIPA (5.0 volumes) at 25-35°C. The solvent was distilled on rotary evaporator at 25-35°C to obtain form-M of Anagrelide hydrochloride monohydrate.

Example 7

Preparation of form-L of Anagrelide hydrochloride monohydrate Anagrelide hydrochloride monohydrate (1.0 equivalent) was dissolved in TFA (5.0 volumes) at 35-40°C. The solvent was distilled on rotary evaporator at 35-40°C to obtain form-L of Anagrelide hydrochloride monohydrate.