The present invention provides a process for the preparation of (-) pramipexole or an acid addition salt thereof of Formula I(Formula Removed)
The present invention further provides novel polymorphic Forms A and B of anhydrous pramipexole dihydrochloride.
Pramipexole of Formula I is chemically (S)-2-amino-4,5,6,7-tetra-hydro-6-(propylamino)benzothiazole and is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease. Pramipexole is commercially available in the form of dihydrochloride salt as monohydrate.
US patent No. 4,886,812 discloses pramipexole or an acid addition salt thereof. The '812 patent further provides various processes for the preparation of pramipexole.
Journal of medical chemistry, 30, 494-498, (1987), describes a process for the preparation of optically pure pramipexole. It also discloses a process for resolution of racemic 2,6-diamino intermediate using L-(+)-tartaric acid as chiral auxiliary. The so obtained single enantiomer precursor is further converted to pramipexole by a two-step reaction, which involves N-acylation and reduction.
PCT patent application No. WO 02/022590 provides a process for preparation of pramipexole which involves reacting 6-substituted 2-amino-4,5,6,7-tetrahydrobenzothiazole with an amine in the presence of a reducing agent. The 6-substituted group may be an alkoxy, alkylenedioxy or an oxo group.
PCT patent application No. WO 02/022591 provides a process for resolution of pramipexole, which involves reacting racemic pramipexole with a acid to form a
monobasic acid addition salt which is further converted into the dibasic acid addition salt.
The present inventors have now found a direct and cost-effective process for the preparation of (-) pramipexole or an acid addition salt thereof of Formula I
(Formula Removed)
wherein the process does not require introduction and removal of a protective group, instead the propionyl group serves as a protective group and a direct precursor for the desired propyl group.
Present inventors have further found that pramipexole dihydrochloride exists in anhydrous form having moisture content 1% w/w or less when determined by Karl Fischer analysis. Present inventors have isolated two characteristic forms of anhydrous pramipexole dihydrochloride. These two forms designated as Form A and Form B are stable under normal storage conditions.
The term "compound of Formula I or acid addition salt thereof in the present invention refers to a compound of Formula I or its monobasic or dibasic acid addition salt. The acid addition salt can be selected from inorganic or organic acid addition salt. The dibasic acid addition salt can be a mixed acid addition salt of two different acids. The term also includes hydrates, solvates and enantiomers of compound of Formula I or acid addition salt thereof.
The first aspect of the invention provides a process for the preparation of (-) pramipexole or an acid addition salt thereof of Formula I which comprises of: a) reacting the compound of Formula II
(Formula Removed)
with bromine and thiourea to obtain a compound of formula III or acid addition salt thereof,
(Formula Removed)
b) reducing the compound of Formula III with a reducing agent to obtain a
racemic mixture of compound of Formula I or acid addition salt thereof,
c) resolving compound of Formula I, with chiral auxiliary to get (-) isomer
of compound of Formula I or acid addition salt thereof.
A second aspect of the invention provides a process for the preparation of racemic pramipexole or an acid addition salt thereof which comprises of reducing the compound of Formula III,
(Formula Removed)
Formula III wherein the reducing agent used is borane-tetrahydrofuran complex.
Bromine is added drop wise to a solution of a compound of Formula II in an organic solvent in about 2-5 hours and the mixture is stirred at ambient temperature. The organic solvent includes but not limited to acetic acid, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether or N,N-dimethylformamide. Thiourea is added to the reaction mixture and the resulting
mixture is refluxed for about 1-4 hours. The mixture is cooled and the solid obtained is filtered and washed to provide a compound of Formula III or acid addition salt thereof.
To the solution of compound of Formula III in an organic solvent, a reducing agent is added drop wise under nitrogen at about room temperature. The resulting mixture is stirred at about 35-60°C, cooled and acidified. The solvent includes but not limited to tetrahydrofuran, diethyl ether, diglyme or an alkanol. After the completion of reduction, water followed by concentrated hydrochloric acid is added to the reaction mass and the solvent is evaporated. The aqueous residue is basified and extracted with ethyl acetate. The solid obtained is filtered, washed and air-dried to provide the compound of Formula I.
The 'reducing agent' used is known to a person of ordinary skills in the art through several literature references. Some examples of the reducing agents include borane, borane-tetrahydrofuran, borane-dimethyl sulfide, sodium borohydride and Boron triflouride-etherate complex and the like. The racemic compound of Formula I is resolved using a chiral auxiliary to obtain (-) isomer of Formula I or acid addition salt thereof.
A third aspect of the present invention provides anhydrous pramipexole dihydrochloride characterized by having moisture content 1% or less when measured by Karl Fischer method.
A fourth aspect of the present invention provides polymorphic Form A of anhydrous pramipexole dihydrochloride having X-Ray Powder Diffraction (XRD) pattern as depicted in Figure 1 of the accompanied drawing wherein characteristic 20 values are obtained at 6.02, 6.40, 6.66, 12.10, 12.78, 13.64, 14.08, 14.56, 14.92, 15.54, 17.16, 17.88, 18.20, 18.42, 19.24, 19.58, 20.00, 20.54, 20.80, 21.78, 23.08, 23.46, 23.60, 24.08, 24.84, 25.74, 26.18, 26.54, 26.86, 27.22, 27.54, 27.86, 28.44, 29.10, 29.42, 30.00, 30.82, 31.40, 31.98,
32.30, 32.86, 33.74, 34.58, 35.04, 35.24, 35.62, 36.04, 37.40, 37.64, 38.78. The polymorphic Form A of anhydrous pramipexole dihydrochloride has characteristic Differential Scanning Calorimetric (DSC) thermogram as depicted in Figure 2 of the accompanied drawing wherein the characteristic endothermic absorptions are observed between 220-310°C and 315-350°C. Form A of anhydrous pramipexole dihydrochloride has moisture content of about 1% or less.
A fifth aspect of the present invention provides polymorphic Form B of anhydrous pramipexole dihydrochloride having X-Ray Powder Diffraction (XRD) pattern as depicted in Figure 3 of the accompanied drawing wherein characteristic 29 values are obtained at 6.32, 6.58, 6.80, 12.04, 12.72, 12.96, 13.56, 13.98, 14.52, 14.86, 15.48, 15.80, 17.10, 17.82, 18.14, 18.36, 19.22, 19.54, 19.84, 19.96, 20.46, 20.72, 21.72, 22.38, 22.90, 23.10, 23.52, 24.04, 24.32, 24.78, 25.02, 25.68, 26.20, 26.46, 26.80, 27.14, 27.76, 28.36, 29.02, 29.38, 29.58, 29.88, 30.74, 31.32, 31.84, 32.22, 32.84, 33.66, 34.38, 34.92, 35.12, 35.56, 35.96, 36.44, 37.32, 37.60, 38.30, 38.72. The polymorphic Form B of anhydrous pramipexole dihydrochloride has characteristic Differential Scanning Calorimetric (DSC) thermogram as depicted in Figure 4 of the accompanied drawing wherein the characteristic endothermic absorptions are observed between 90-120°C and 255-310°C
A sixth aspect of the present invention provides pramipexole dibasic acid addition salt having less than detectable quantity of monobasic acid addition salt. In order to incorporate pramipexole or salt thereof in the finished dosage form it is very important to know the exact content of the pramipexole base in the bulk active. Pramipexole has a tendency to form monobasic as well as dibasic acid addition salts with organic or inorganic acids. The approved drug in the market is pramipexole dihydrochloride which is dibasic acid addition salt with hydrochloric acid. A contamination with monobasic acid addition salt in dibasic acid addition salt would complicate the issue for formulation chemist as he would not be exactly weigh the required bulk active in order to prepare finished dosage form.
Figure 1 depicts the X-Ray Diffraction Pattern (XRD) of polymorphic Form A of
anhydrous pramipexole dihydrochloride.
Figure 2 depicts Differential Scanning Calorimetric (DSC) thermogram of
polymorphic Form A of anhydrous pramipexole dihydrochloride.
Figure 3 depicts the X-Ray Diffraction Pattern (XRD) of polymorphic Form B of
anhydrous pramipexole dihydrochloride.
Figure 4 depicts Differential Scanning Calorimetric (DSC) thermogram of
polymorphic Form B of anhydrous pramipexole dihydrochloride.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1 Preparation of 4-Propionamide cyclohexanol
To a solution of 4-amino cyclohexanol (100 g) in dichloromethane (2000 ml).at 5-10°C propionic anhydride (114 g) was added drop wise in 1 hour. The temperature was raised to 20-25°C and reaction mixture was stirred at this temperature for 5-6 hours. After completion of the reaction, the mixture was cooled to 5-10°C and filtered to obtain the title compound.
Example 2 Preparation of 4-Propionamido cyclohexanone
To a solution of 4-propionamido-cyclohexanol (100 g) in acetone (1000 ml), Jones Reagent (prepared from chromic acid (66.54 g), sulphuric acid (96.28 g) and water (400 ml)) was added at 5-10°C. The mixture was stirred for 5-6 hours. After completion of the reaction, excess reagent was quenched by addition of
isopropanol (400 ml). The residue of Jones reagent was filtered and the solid was washed with ethyl acetate (100 ml X 3). The solvent was removed under reduced pressure and the residue was again extracted with ethyl acetate (200 ml X 3). The contents were stirred for 30 minutes at 45-50°C and the upper portion was decanted and concentrated completely under vacuum to obtain a solid. To the residue ethyl acetate (100 ml) was charged and stirred at 45-50°C for 30 minutes to get clear solution and then hexane (200 ml) was charged. The mixture was cooled to 0-5°C in 2 hours and filtered at 0-5°C to get the title compound.
Example 3 Preparation of 2-amino-6-propionylamino-4,5,6,7-tetrahydro benzothiazole
Bromine (160 g) was added dropwise to a solution of 4-propionamido-cyclohexanone (155 g) in glacial acetic acid (1500 ml) in 3 hours and the mixture was stirred for 1-2 hours at ambient temperature. Thiourea (152.0 g) was added to the reaction mixture and the resulting mixture was refluxed for 2-3 hours. After cooling, the crystals of 2-amino-6-(N-propionamido)-4,5,6,7-tetrahydro-benzothiazole-hydrobromide precipitated was filtered and washed with ethyl acetate.
2-amino-6-(N-propionamido)-4,5,6,7-tetrahydro-benzothiazole-hydrobromide was charged to water (620 ml) to get a clear solution. To this 50 % sodium hydroxide solution (39 g in 110 ml water) was added dropwise at 5-10°C. The solid precipitated was filtered and washed with isopropanol (155 ml) to get the title compound.
Example 4
Preparation of (±)-2-Amino-6-(N-propylamino)-4,5,6,7-tetrahydro
benzothiazole
To a solution of 2-amino-6-(N-propionamido)-4,5,6,7-tetrahydro-benzothiazole (2.25 g) in anhydrous tetrahydrofuran (25 ml) was added borane-tetrahydrofuran
complex (50 ml, 1M solution in tetrahydrofuran) drop wise under nitrogen at room temperature. The resulting mixture was stirred at 50°C for 1 hour, cooled, and then water (5 ml) and concentrated aqueous hydrochloric acid (10 ml) were added. The tetrahydrofuran was evaporated and 25% aqueous Sodium hydroxide (30 ml) was added to the water phase. The desired compound was extracted from the reaction mixture by using ethyl acetate (100 ml x 3). The organic phase was dried and concentrated. Hexane (10 ml) was added to the resulting oily residue and stirred for 15 minutes. The solid obtained was filtered and air-dried to get the title compound. Yield: 1.9 g
Example 5
Preparation of (-)-2-Amino-6-(N-propylamino)-4,5,6,7-tetrahydro benzothiazole-dihydrochloride
(a) Preparation of (±)-2-amino-6-(N-propylamino-4,5,6,7-tetrahydrobenzo
thiazole monohydrochloride
((±)-2-amino-6-(N-propylmamino)-4,5,6,7-tetrahydrobenzothiazole (4.2 g) was dissolved in hot methanol (15 ml) and hydrochloric acid (1.65 ml) was added. The obtained suspension was stirred, cooled and precipitated solid was filtered off. The cake was washed with cold methanol and air-dried to give the title compound. Yield: 4.2 g
(b) A mixed salt of pramipexole monohydrochloride with L-(+)-tartaric acid
(±)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole monohydrochloride was dissolved in hot methanol (23 ml) and L-(+)-tartaric acid (1.80 g) was added. White crystals precipitated, the mixture was cooled and crystals were removed by suction, washed with cold methanol and dried to give a solid, which was recrystallized from hot methanol to give the title compound. Yield: 2.2 g
(c) Liberation of (S)-Pramipexole freebase
Pramipexole monohydrochloride monotartrate from the step (b) was dissolved in water (10 ml) and cooled to 10°C, and solution of potassium hydroxide (5g in 10 ml Dl water) was added. The mixture was stirred at 10°C for 30 minutes and the white crystals were filtered and washed with cold water. The cake was dried to give white crystals of the title compound. Yield: 0.95 g
(d) (S)-Pramipexole dihydrochloride
The crystals from the step (c) were dissolved in ethanol (7 ml) and ethanolic
hydrochloride was added dropwise at 10°C and the mixture was stirred at 10°C
for 1 hour. The crystals formed were filtered and washed with cold methanol. The
cake was dried to give of white crystals of the title compound.
Yield: 1.1 g
Pramipexole monohydrochloride: Not detectable.

WE CLAIM:
1. A process for the preparation of (-) pramipexole or an acid addition salt thereof
of Formula I which comprises of:
a) reacting the compound of Formula II
(Formula Removed)
with bromine and thiourea to obtain a compound of formula III or acid addition salt thereof,
(Formula Removed)
b) reducing the compound of Formula III with a reducing agent to obtain a
racemic mixture of compound of Formula I or acid addition salt thereof,
c) resolving compound of Formula I, with chiral auxiliary to get (-) isomer
of compound of Formula I or acid a salt thereof.

2. A process according to claims 1, wherein the reducing agent used is borane-
tetrahydrofuran complex.
3. A process according to claim 1 wherein in step a) the organic solvent is
selected from group comprising of acetic acid, chloroform, carbon tetrachloride,
tetrahydrofuran, diethyl ether or N,N-dimethylformamide.
4. A process for the preparation of racemic pramipexole or an acid addition salt
thereof which comprises of reducing the compound of Formula III,
(Formula Removed)
wherein the reducing agent used is boron-tetrahydrofuran complex.
5. Anhydrous pramipexole dihydrochloride having moisture content of 1% or less
when measured by Karl Fischer method.
6. Polymorphic Form A of anhydrous pramipexole dihydrochloride.
7. Polymorphic Form A of anhydrous pramipexole dihydrochloride having a XRD
pattern wherein characteristic 20 values are obtained at 6.02, 6.40, 6.66, 12.10,
12.78, 13.64, 14.08, 14.56, 14.92, 15.54, 17.16, 17.88, 18.20, 18.42, 19.24,
19.58, 20.00, 20.54, 20.80, 21.78, 23.08, 23.46, 23.60, 24.08, 24.84, 25.74,
26.18, 26.54, 26.86, 27.22, 27.54, 27.86, 28.44, 29.10, 29.42, 30.00, 30.82,
31.40, 31.98, 32.30, 32.86, 33.74, 34.58, 35.04, 35.24, 35.62, 36.04, 37.40,
37.64, 38.78.
8. Polymorphic Form A of anhydrous pramipexole dihydrochloride having
characteristic endothermic peaks at 220-310°C and 315-350°C in DSC.
9. Polymorphic Form B of anhydrous pramipexole dihydrochloride.
10. Polymorphic Form B of anhydrous pramipexole dihydrochloride having a
XRD pattern wherein characteristic 20 values are obtained at 6.32, 6.58, 6.80,
12.04, 12.72, 12.96, 13.56, 13.98, 14.52, 14.86, 15.48, 15.80, 17.10, 17.82,
18.14, 18.36, 19.22, 19.54, 19.84, 19.96, 20.46, 20.72, 21.72, 22.38, 22.90,
23.10, 23.52, 24.04, 24.32, 24.78, 25.02, 25.68, 26.20, 26.46, 26.80, 27.14,
27.76, 28.36, 29.02, 29.38, 29.58, 29.88, 30.74, 31.32, 31.84, 32.22, 32.84,
33.66, 34.38, 34.92, 35.12, 35.56, 35.96, 36.44, 37.32, 37.60, 38.30, 38.72.
11. Polymorphic Form B of anhydrous pramipexole dihydrochloride having
characteristic endothermic peaks at 90-120°C and 255-310°C in DSC.
12. Pramipexole dibasic acid addition salt having less than detectable quantity of
monobasic acid addition salt.
13. A pharmaceutical composition comprising anhydrous pramipexole
dihydrochloride along with a pharmaceutically acceptable carrier or diluent.
14. A pharmaceutical composition comprising Pramipexole dibasic acid addition
salt having less than detectable quantity of monobasic acid addition salt along
with a pharmaceutically acceptable carrier or diluent.
15. A method of treating the signs and symptoms of idiopathic Parkinson's
disease which comprises of administering to a mammal in need thereof a
therapeutically effective amount of anhydrous pramipexole dihydrochloride.
16. A method of treating the signs and symptoms of idiopathic Parkinson's
disease which comprises of administering to a mammal in need thereof a
therapeutically effective amount of Pramipexole dibasic acid addition salt having
less than detectable quantity of monobasic acid addition salt.