CLIAMS:We Claim:

1. An improved process for the preparation of pramipexole or its salt, which comprises:

a) reaction of (S)-2,6-diamino-4,5,6,7-tetra-hydrobenzothiazole with 1 to 1.2 molar equivalents of propionaldehyde using 1 to 1.2 molar equivalents of sodium borohydride in presence of alcohol and acetic acid at a temperature of about -12 to -6 ºC;

b) addition of 1 to 3 molar equivalents of propionaldehyde and 1 to 3 molar equivalents of sodium borohydride to the reaction mixture of step a) at a temperature of about -12 to -6 ºC; and

c) purification of the compound of step b) from acetonitrile having moisture content greater than 1% to provide pramipexole or its salt substantially free from its impurity C of Formula 2.

Formula 2
2. The process of claim 1, wherein the alcohol of step a) is methanol.

3. The process of claim 1, wherein the amount of acetic acid is 0.01 to 0.04 molar equivalents with respect to (S)-2,6-diamino-4,5,6,7-tetra-hydrobenzothiazole.

4. The process of claim 1, wherein the amount of acetic acid is 0.035 molar equivalents with respect to (S)-2,6-diamino-4,5,6,7-tetra-hydrobenzothiazole.

5. The process of claim 1, wherein the amount of propionaldehyde of step a) range from 1 to 1.12 equivalents with respect to (S)-2,6-diamino-4,5,6,7-tetra-hydrobenzothiazole.

6. The process of claim 1, wherein the amount of sodium borohydride of step a) range from 1 to 1.12 equivalents with respect to (S)-2,6-diamino-4,5,6,7-tetra-hydrobenzothiazole.

7. The process of step claim 1, wherein the reaction of step a) is stirred at 10 to 15 ºC for 10 minutes or more.

8. The process of claim 1, wherein the moisture content of acetonitrile of step c) is 2%.

9. The process of claim 1, wherein the purification process for pramipexole or its salt comprises:

a) providing solution of crude pramipexole or its salt in moisturized acetonitrile having moisture content greater than or equal to 1%;
b) distilling out the solvent of the step a) to certain volume;
c) stirring the reaction mixture of step b) at room temperature for a period of 1 hour or more; and
d) filtering the solid from the step c) to provide pramipexole or its salt substantially free from its impurity C of Formula 2.

Formula 2
10. The process of claim 1, wherein the pramipexole impurity C of Formula 2 in pramipexole or its salt is less than 0.15%.

Formula 2
,TagSPECI:3. PREAMBLE TO THE DESCRIPTIONThe present invention provides an industrially advantageous process for the preparation of Pramipexole or its salt substantially free from its impurities.
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention

The present invention relates to a process for the preparation of pramipexole or its salt which avoids or reduces the formation of impurities. The present invention relates to an improved process to provide Pramipexole or its salt having impurity C less than or equal to 0.15%.

Background of the invention

Pramipexole dihydrochloride, chemically known as (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride, is a synthetic aminobenzothiazole derivative having the structural formula 1, which is marketed under the trade name Mirapex®.

Formula 1

The drug is a dopamine agonist used for treating Parkinson's disease by stimulating the dopamine receptors in the brain. Pramipexole is listed in the EP Pharmacopeia and it contains impurities A, B, C, D and E.

Various synthetic routes for preparing pramipexole, its salts thereof and the intermediates thereof were previously described in European Pat Nos. 186087 and 207696; U.S Pat. Nos 6727367 and 6770761; and international Pat applications WO 2004/026850, WO 2004/041797 and WO 2005/014562. An additional synthetic route was disclosed by CS Schneider and J. Mierau in J. Med. Chem., 1987, 30, 494-498.

WO 2006070349 discloses a process for preparation of pramipexole base comprising reacting the starting material (S)-2,6-diamino-4,5,6,7-tetra-hydrobenzothiazole with propionaldehyde in an organic solvent and a reducing agent sodium triacetoxyborohydride [NaB(O2CCH3)H] thus avoiding the usage of borane tetrahydrofuran complex. The yields of pramipexole base obtained by carrying out the reactions at a temperature of around 50C as in (Example 1) or -150C as in (Example 4) are 69% and 55% respectively and also 20% formation of undesirable (R,S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole.

Indian patent application 605/MUM/2008 discloses a process for preparation of pramipexole base wherein the reaction of the starting material (S)-2, 6-diamino-4, 5, 6, 7-tetra-hydrobenzothiazole is with propionaldehyde in an organic solvent and addition of reagents sodium borohydride and anhydrous acetic acid in more than one lot maintaining reaction temperatures at 0ºC to -6 ºC.

WO 2006/003677 discloses a process for the preparation of Pramipexole from the reaction of (S)-2, 6-diamino-4, 5, 6, 7-tetra-hydrobenzothiazole and propionaldehyde in presence of sodium borohydrate, sulfuric acid and methanol, followed by crystallization from acetonitrile. The reaction involves addition of propinaldehyde and sodium borohydrate in 2 lots, first lot is added at 0 ºC and second lot is added at 25 ºC.

Indian patent application 2069/MUM/2010 discloses process for Pramipexole wherein the reaction conducted at -10 to 0 ºC in presence of sodium borohydrate, sulfuric acid and methanol and involved addition of propionaldehydedehyde in 4-5 lots.

The inventors of the present invention found that none of the prior art processes provides pramipexole or its salt having content of impurity C less than 1.0% from the reaction.

Therefore, there is a need to develop an improved and industrially feasible process for providing Pramipexole or its salt to eliminate or to reduce the formation of impurity C of Pramipexole.

Summary of the Invention

The present invention provides a process for the preparation of Pramipexole or its salt having reduced impurities specifically impurity C by the use of selective and specific reaction conditions such as addition of reagent in lot-wise, control on the moisture content of the reaction, use of acetic acid and use of temperature of about -12 to about -6 ºC for addition.

In an aspect, the present invention is to provide an improved process for the preparation of pramipexole or its salt, which comprises:

a) reaction of (S)-2,6-diamino-4,5,6,7-tetra-hydrobenzothiazole with 1 to 1.2 molar equivalents of propionaldehyde using 1 to 1.2 molar equivalents of sodium borohydride in presence of alcohol and acetic acid at a temperature of about -12 to -6 ºC;

b) addition of 1 to 3 molar equivalents of propionaldehyde and 1 to 3 molar equivalents of sodium borohydride to the reaction mixture of step a) at a temperature of about -12 to -6 ºC; and

c) purification of the compound of step b) from acetonitrile having moisture content greater than 1% to provide pramipexole or its salt substantially free from its impurity C.

In another aspect, the present invention provides a process for the purification of pramipexole or its salt substantially free from its impurity C, which comprises:

a) providing solution of crude pramipexole or its salt in moisturized acetonitrile having moisture content greater than or equal to 1%;
b) distilling out the solvent of the step a) to certain volume;
c) stirring the reaction mixture of step b) at room temperature for a period of 1 hour or more; and
d) filtering the solid from the step c) to provide pramipexole or its salt substantially free from its impurity C.

Description of the Invention
The term “lot-wise” as used herein, unless otherwise defined, means the addition of propionaldehyde and sodium borohydrate may be done twice or more while the total specific reagent remains the same, though the reagent addition may be equal or unequal in each lot and the process of addition may or may not be in small proportions.

The term “one lot” as used herein, unless otherwise defined, regard to reagent addition may mean the addition of total specific reagent only once which may or may not be in small proportions.

“Reagent” as used herein, unless otherwise defined, may mean any one of the reagents such as propionaldehyde, sodium hydro bromide.

“Quantity” of reagent as used herein, unless otherwise defined, in regard to reagent addition may mean the addition of total quantity of that reagent in one lot or two lots while carrying the reaction.

The term “moisturized acetonitrile” as used herein, unless otherwise defined, refers to acetonitrile solvent that contains moisture greater than or equal to 1%.

The term “crude pramipexole or its salt” as used herein, unless otherwise defined, refers to pramipexole or its salt that contains impurity C greater than or equal to 0.2 or greater than or equal to 0.5%.

The term “substantially free” as used herein, unless otherwise defined, refers to pramipexole or its salt that contains impurity C less than 0.15%.

Pramipexole impurity C of the present invention is represented by Formula 2.

Formula 2

The advantages of the process of preparation of pramipexole or its salt of the present invention:
(i) limit the overall impurity content to not more than 0.15% by limiting pramipexole impurity C formation;
(ii) improves the yield and purity;
(iii) improves the quality of product by removed color impurities directly without involving any additional purification technique; and
(iv) commercially and industrially more economical and viable one.

In an aspect, the present invention is to provide an improved process for the preparation of pramipexole or its salt, which comprises:

a) reaction of (S)-2,6-diamino-4,5,6,7-tetra-hydrobenzothiazole with 1 to 1.2 molar equivalents of propionaldehyde using 1 to 1.2 molar equivalents of sodium borohydride in presence of alcohol and acetic acid at a temperature of about -12 to -6 ºC;

b) addition of 1 to 3 molar equivalents of propionaldehyde and 1 to 3 molar equivalents of sodium borohydride to the reaction mixture of step a) at a temperature of about -12 to -6 ºC; and

c) purification of the compound of step b) from acetonitrile having moisture content greater than 1% to provide pramipexole or its salt substantially free from its impurity C of Formula 2.

Formula 2
In an embodiment, the present invention comprises a process for the preparation of pramipexole or its salt by reaction of charcoalised starting material S (-) 2, 6-diamino-4, 5, 6, 7-tetrahydrobenzothiazole in alcohol with propanal, sodium borohydride wherein the reaction is allowed to proceed in two phases at a temperature range of -12ºC to -6ºC by adding the reagents in two lots to avoid or limit the extent of formation of pramipexole impurity C to less than 2% in crude pramipexole free base.

The overall process for pramipexole or its alt is depicted in the following scheme:

The step a) involves a) reaction of (S)-2,6-diamino-4,5,6,7-tetra-hydrobenzothiazole with 1 to 1.2 molar equivalents of propionaldehyde using 1 to 1.2 molar equivalents of sodium borohydride in presence of alcohol and acetic acid at a temperature of about -12 to -6 ºC.

The alcohol used for the step a) includes methanol, ethanol, isopropyl alcohol, n-butanol and the like.

The amount of acetic acid used for step a) is about 0.01 to 0.04 molar equivalents or 0.035 molar equivalents with respect to (S)-2, 6-diamino-4, 5, 6, 7-tetra-hydrobenzothiazole.

Propionaldehyde (1 to 1.2 molar equivalents per equivalent of starting material) is added drop wise for a period of 25-30 minutes followed by sodium borohydride (1 to 1.2 molar equivalents per equivalent of starting material) is added for a period of 90-120 minutes to the (S)-2, 6-diamino-4, 5, 6, 7-tetra-hydrobenzothiazole in methanol to avoid the exothermic reaction.

Addition of propanal and sodium borohydride of the present invention is performed at a temperature range of -12 ºC to -6 ºC and the then the reaction mass stirred at 10 ºC to 15 ºC for 10 minutes or more.

Carrying out the reaction of step a) by adding the reagent quantities mentioned in the first step (i.e. step a) while maintaining temperature range of -12ºC to -6ºC improves the quality and reduces or avoids the formation of pramipexole impurity C to a value of about 0-0.6% (S. No 4 in Table 1) which other wise would have been either 0.96% or 2.2% at higher reagent quantity addition or higher temperature or a combination both as may be seen in S. No 1 and 2 in Table 1.

Table 1 summarizes the pramipexole impurity C formation at various reagent quantities and at different reaction temperatures.

Table 1
S. No propanal (Kg)Per Kg Input NaBH4 (kg) Per Kg input Impurity C In crude (%) Reaction temperature (ºC)
1 0.48 (1.39 molar equivalents) 0.32 (1.43 molar equivalents) 2.2 (-6) to (0)
2 0.48 (1.39 molar equivalents) 0.32 (1.43 molar equivalents) 0.96 (-12) to (-6)
3 0.43 (1.25 molar equivalents) 0.28 (; 1.25 molar equivalents) 1.09 (-12) to (-6)
4 0.38 (1.12 molar equivalents) 0.25 (1.118 molar equivalents) 0.61 (-12) to (-6)
5 0.36 (1.049 molar equivalents) 0.24 (1.07 molar equivalents) 0.59 (-12) to (-6)

One of the main advantages in limiting the pramipexole impurity C formation during the step a) by decreasing the additions of reagents i.e. propanal and sodium borohydride as shown in the table 1 from the normal circumstances of the prior art is to provide effective reaction condition to avoid further formation or increase of pramipexole impurity C even if the reagent addition is more during the step b) reaction. Further this control on pramipexole impurity C formation during the first lot reagent addition reaction stage may ensure obtaining the pramipexole free base comprising the impurity not more than 0.15% in the ultimate besides reduction in the load during purification stage.

The use of specific reagent quantity during the step a) of the present invention limit the formation of pramipexole impurity C in pramipexole or its salt which may ultimately limit the total impurities not more than 0.15% in purified pramipexole or its salt.

The obtained reaction mixture of step a) is subjected for stirring of about 10 minutes or more at a temperature of about 10 to about 15 ºC and then cooled to -12 to -6 ºC for further reactions.

The step b) involves addition of 1 to 3 molar equivalents of propionaldehyde and 1 to 3 molar equivalents of sodium borohydride to the reaction mixture of step a) at a temperature of about -12 to -6 ºC.

The addition of propanal to the reaction mixture of step a) may be added in about 30-45 minutes followed by addition of sodium borohydride drop wise maintaining a temperature range of (-12ºC ) to (-6ºC).

After the reaction completion, the reaction mass may be quenched by brine solution and distilling out methanol. The mixture may be extracted with ethyl acetate and organic layer may be concentrated to obtain crude pramipexole or its salt.

The step c) involves purification of the compound of step b) from acetonitrile having moisture content greater than 1% to provide pramipexole or its salt substantially free from its impurity C.

The purification process of crude pramipexole or its salt involves providing solution of obtained compound from step b) in the moisturized acetonitrile at elevated temperature, for example, reflux temperature and distilling it out to certain amount. The reaction mass may be cooled to room temperature, stirred for a certain period of time, for example, about 1 to 2 hours or more, filtered and then washed the solid with acetonitrile.

The purification step (c) may be repeated once again to improve the quality of pramipexole or its salt and to reduce the impurity content in Pramipexole or its salt.

The obtained pramipexole or its salt of the present invention has the purity greater than about 95 % or greater than about 99% and has impurity content, especially impurity C, less than 0.15% determined by HPLC.

In another aspect, the present invention provides a process for the purification of pramipexole or its salt substantially free from its impurity C of Formula 2, which comprises:

Formula 2
a) providing solution of crude pramipexole or its salt in moisturized acetonitrile having moisture content greater than or equal to 1%;
b) distilling out the solvent of the step a) to certain volume;
c) stirring the reaction mixture of step b) at room temperature for a period of 1 hour or more; and
d) filtering the solid from the step c) to provide pramipexole or its salt substantially free from its impurity C.

The solvent, moisturized acetonitrile may be used 4 to 5 times in volume for providing solution crude pramipexole or its salt. The solution is prepared by increasing the temperature to an elevated temperature, for example, to a reflux temperature.

The obtained solution is distilled out for example, 1/3rd of the solvent from the solution and then cooled to room temperature to initiate the precipitation and to reduce the moisture content in the reaction mixture. The obtained reaction mixture may be stirred for a period of 1 to 2 hours or more to increase the solidification from the reaction mixture. The obtained suspension is filtered and dried to obtain pramipexole or its salt substantially free from its impurities.

The use of moisturized acetonitrile for purification process of the present invention plays an important role in removing the pramipexole impurity C from the crude pramipexole or its salt. As shown in Table 2, crude pramipexole or its salt obtained by addition of reagents given in S. No 1 in Table 1 having pramipexole impurity C of 2.2% is purified by refluxing with 2% moisturized acetonitrile to obtain pramipexole impurity C of around 0.09%.

The sensitivity to percentage of moisture in acetonitrile used in the purification process of the present invention on the pramipexole impurity C in the purified pramipexole or its salt is tabulated in Table 2.

Table 2
S. No Moisture in acetonitrile (%) % Pramipexole Impurity Impurity removal (%)
Initial *RC-1 *RC-2
1 2 2.2 0.19 0.09 96
2 1 1.02 0.18 0.08 92
3 2 0.65 0.22 0.11 99
4 0.5 1.09 0.64 0.32 70
RC-1: First crystallization.
RC-2: Second Recrytalliazation.
It may be observed that at moisture content of 0.5% in acetonitrile the extent of pramipexole impurity C removal may about 70% of the impurity present in the crude pramipexole or its salt resulting in purified pramipexole or its salt still having pramipexole C impurity of 0.3 much above the desirable value of 0.15%. The pramipexole impurity C in the purified pramipexole or its salt after two successive crystallizations may decrease to 0.08% and 0.11% when purification may be carried out at 1.0% and 2.0% moisture content in acetonitrile as shown in Table 2.

The salt of the pramipexole of the present invention may be hydrochloride, hydrobromide, formic acid, acetic acid, tartaric acid and the like.

The resultant pramipexole or its salt may be converted into pramipexole dihydrochloride using ethanolic HCl in presence of ethanol and then to pramipexole dihydrochloride monohydrate from ethanol, water and ethyl acetate as disclosed in the art. The same is depicted in the following scheme:

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES
Example 1: A process for preparation of pramipexole

To a stirred solution of charcoalised S-(-)2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (1.0 Kg) methanol (1.0 L) in water, propanal (0.38 Kg) was added drop wise at -120C to -60C. After stirring for 25-30 min, a catalytic amount of acetic acid was added followed by sodium borohydride (0.25 Kg) at temperature of -120C to -60C and stirred at 10-15 0 C. Second lot of propanal (0.651 Kg) was added at -120C to -60C temperature in 30-45 minutes followed by sodium borohydride (0.401 Kg) lot-wise at -120C to -60C. After the completion of reaction, the reaction mixture is quenched by brine solution and then methanol was distilled out. The mixture was extracted into ethyl acetate and then concentrated to provide crude Pramipexole freebase.

The obtained crude was purified by dissolving in moisturized acetonitrile (4.7 times) at reflux temperature and then distilled off the solvent (2 to 2.2 times). The reaction mass was cooled to room temperature, stirred for 90 to 120 minutes to provide suspension. The solid was filtered, washed with acetonitrile and then dried at 55 to 60 0C for a period of 2 to 3 hours.

The purification process was repeated once again to improve the quality of pramipexole and to reduce the impurity content in Pramipexole or its salt.

Purity by HPLC: 99.83 %
Impurity C content: 0.09%
Yield: 0.85 Kg.

The same purification process may also be utilized to purify the salt of pramipexole, especially pramipexole dihydrochloride, directly without isolating free base to afford purity greater than 99.8% by HPLC.