EP1926486A1

EP1926486A1 - Novel polymorphs of (s)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate and methods of producing and using the same

Info

Publication number: EP1926486A1
Application number: EP05798176A
Authority: EP
Inventors: Itai Adin; Michael Brand; Carmen Iustain
Original assignee: Chemagis Ltd
Current assignee: Wavelength Enterprises Ltd
Priority date: 2005-09-21
Filing date: 2005-09-21
Publication date: 2008-06-04
Also published as: EP1926486A4; WO2007040474A1

Abstract

Provided are crystalline forms of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate (DIAT), including DIAT form I, DIAT form II, and DIAT form III. Also provided are methods for preparing DIAT form I, DIAT form II, and DIAT form III, and methods for preparing pramipexole therewith.

Description

NOVEL POLYMORPHS OF (S)-2,6-DIAMINO-4,5,6,7-

TETRAHYDROBENZOTHIAZOLE MONOTARTRATE AND METHODS OF

PRODUCING AND USING THE SAME

BACKGROUND OF THE INVENTION

[0001] Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra (an area in the basal ganglia) and resulting in slowing of emotional and voluntary movement, muscular rigidity, postural abnormality and tremor. Therapy has focused on replacing depleted dopamine via supplementation with L-dopa or dopamine agonists such as pramipexole, ropinirole, lisuride, cabergoline, apomorphine, pergolide or bromocriptine.

[0002] Pramipexole dihydrochloride, (5)-2-amino-4,5,6,7-tetrahydro-6-

(propylamino)benzothiazole, is a synthetic aminobenzothiazole derivative, marketed under the trade name Mirapex , represented by molecular formula 1 :

• 2 HCl 1

[0003] Various synthetic routes for preparing pramipexole, salts and intermediates thereof, were previously described in European Pat. Nos. EP 186087 and EP 207696; U.S Pat. Nos. 4,731,374, 6,727,367 and 6,770,761; and international patent applications WO 2004/026850 and WO 2004/041797.

[0004] An additional synthetic route was disclosed by Schneider et al., J Med.

Chem., 30, 494-498 (1987). According to this route, pramipexole is prepared from (iS)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate (formula 2), as illustrated in scheme 1 : Scheme 1

(5)-2,6-diamino-4,5,6,7-tetrahydro- benzothiazole monotartrate (DIAT)

B₂H₆

pramiprexole base

[0005] According to the description in Schneider et al., J Med. Chem., 30, 494-

498 (1987), (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate is prepared by resolution of the racemic diamine with L-(+)-tartaric acid, to afford (S)-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate. The (5)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate is then alkylated (in this case via conversion to the propionamide followed by reduction of the amide) to produce (S)-2-amino- 4,5,6,7-tetrahydro-6-(propylamino)benzothiazole (pramipexole). [0006] There is a need for stable forms of (>S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate, which can facilitate the production of pramipexole. The present invention provides stable, crystalline forms of (5)-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate, which can facilitate the production of pramipexole.

BRIEF SUMMARY OF THE INVENTION

[0007] The present invention provides stable crystalline forms of (S)-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate ("DIAT"). The crystalline forms of the present invention preferably include DIAT form I, DIAT form II and DIAT form III, as described herein.

[0008] The present invention provides a method for producing DIAT form I, which method includes crystallizing DIAT from a solution, which is preferably an aqueous solution, e.g., water or a mixture of water and one or more organic solvents. In one embodiment, DIAT form I is prepared by crystallizing DIAT from a mixture of water and at least one polar organic solvent, which is preferably selected from the group consisting of methanol, ethanol, acetonitrile and combinations thereof, to produce DIAT form I. Optionally, the crystallization can be carried out in the presence of one or more amino acids (e.g., about 1% (1 wt%) of one or more amino acids) in the solution, to produce DIAT form I. Surprisingly, it has been found that the inclusion of one or more amino acids in the crystallization solution produces large crystals, e.g., large single crystals, of DIAT form I.

[0009] The present invention also provides a method for producing DIAT form

II, which method includes crystallizing DIAT from a mixture of water and at least one organic solvent, which is preferably selected from the group consisting of isopropanol, ethyl acetate and combinations thereof. The present invention additionally provides a method for producing DIAT form II, which method includes drying DIAT form I at elevated temperature, optionally under reduced pressure, to produce DIAT form II.

[0010] The present invention further provides a method for producing DIAT form III, which method includes drying DIAT form II at elevated temperature to produce DIAT form III.

[0011] The present invention still further provides a method of producing pramipexole by converting DIAT form I, DIAT form II, DIAT form III, or a combination thereof, into pramipexole (which includes pramipexole free base and salts thereof, e.g., pharmaceutically acceptable salts such as, e.g., the monohydrochloride or dihydrochloride). In accordance with the present invention, DIAT form I, DIAT form II, DIAT form III, or a combination thereof, can be converted into pramipexole using methods that are well known in the art, e.g., by alkylating the 6-amino to produce (5)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole (pramipexole).

[0012] For instance, DIAT form I, DIAT form II, DIAT form III, or any suitable combination thereof, can be converted into pramipexole by alkylating the 6-amino to produce pramipexole. The alkylation can include, e.g., amidating/acylating the 6- amino to produce (S)-2-amino-4,5,6,7-tetrahydro-6-(propionamido)benzothiazole, and reducing the amide to produce (5)-2-amino-4,5,6,7-tetrahydro-6- (propylamino)benzothiazole (pramipexole). See, e.g., Schneider et al., J. Med. Chem., 30, 494-498 (1987).

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 depicts an optical microscopy (x40) image of DIAT form I.

[0014] Figure 2 depicts an optical microscopy (x40) image of DIAT form II.

[0015] Figure 3 depicts an X-ray powder diffraction pattern of DIAT form I.

[0016] Figure 4 depicts an infrared spectrum of DIAT form I.

[0017] Figure 5 depicts a differential scanning calorimetry (DSC) curve of DIAT form I.

[0018] Figure 6 depicts a thermogravimetric analysis (TGA) curve of DIAT form I.

[0019] Figure 7 depicts an X-ray powder diffraction pattern of DIAT form II.

[0020] Figure 8 depicts an alternative X-ray powder diffraction pattern of DIAT form II.

[0021] Figure 9 depicts a DSC curve of DIAT form II.

[0022] Figure 10 depicts a TGA curve of DIAT form II.

[0023] Figure 11 depicts an alternative TGA curve of DIAT form II.

[0024] Figure 12 depicts an X-ray powder diffraction pattern of DIAT form III.

[0025] Figure 13 depicts an infrared spectrum of DIAT form III.

[0026] Figure 14 depicts a DSC curve of DIAT form III.

[0027] Figure 15 depicts a TGA curve of DIAT form III.

DETAILED DESCRIPTION OF THE INVENTION

[0028] DIAT form I produces an X-ray powder diffraction pattern, e.g., as depicted in Figure 3. A peak listing is provided in Table 1. Table 1 DIAT form I - X-ray powder diffraction peak position and intensities

[0029] The strong diffraction peaks at 7.8, 9.3, 13.2, 14.4, 15.7, 17.1, 25.8, 26.9

± 0.2 degrees 2Θ are characteristic of DIAT form I.

[0030] DIAT form I can contain crystals in the shape of long prisms, with narrow to medium width, e.g., as shown in Figure 1. DIAT form I can exist as a hydrate, e.g., containing about 15 ± 2 percent water or about three molar equivalents of water. Upon heating or drying, a phase transformation from DIAT form I to DIAT form II occurs. This transformation is not clearly observed by thermal analysis. While not wishing to be bound by any particular theory, the reason for this phenomenon may be that the transformation takes place simultaneously with water discharge, and the two events overlap in DSC. Preferably, during the transition to form II, no melting is observed throughout the entire temperature range based on the weight loss curve observed in TGA.

[0031] A characteristic DSC curve of DIAT form I (e.g., as illustrated in Figure

5) typically contains three peaks. Typically, the DSC curve of DIAT form I exhibits peaks with onsets at about 120 ⁰C, about 135-140 ⁰C and about 195-200 ⁰C. The intensity of the second peak (low intensity, onset about 135-140 ⁰C) can vary (e.g., can be much larger) depending on the sample preparation. The third peak (onset about 200 ⁰C) is believed to correspond to the melting and decomposition of the in- situ created anhydrous form III. A characteristic TGA curve is depicted in Figure 6. [0032] A characteristic infrared spectrum of DIAT Form I is shown in Figure 4.

The absorption peaks at 1652, 1317 and 978 cm^"1, the broad area between 1500-1600 cm^"1, and the doublet around 800-850 cm^"1 are characteristic bands associated with DIAT form I.

[0033] In accordance with the present invention, DIAT form I can be prepared by a method, which comprises crystallizing DIAT from an aqueous solution containing about 1% of an amino acid, to obtain large single crystals of DIAT form I. An exemplary crystallization process for preparing DIAT form I in the presense of one or more amino acids includes:

(i) refluxing an aqueous solution containing of DIAT and about 1% of an amino acid (or a combination of one or more amino acids);

(ii) allowing the solution to cool sufficiently (preferably to about 25°C) to precipitate crystals of DIAT form I;

(iii) optionally isolating the crystals, e.g., by filtration; and

(iv) optionally drying the crystals (e.g., by placing the crystals in a fume hood and allowing them to dry).

[0034] Any suitable amino acid can be used in the crystallization process of the invention. Suitable amino acids can include natural as well as synthetic amino acids, e.g., L-amino acids, D-amino acids or DL-amino acids. Exemplary amino acids can include one or more amino acids selected from the group consisting of L-alanine, L- tyrosine, D-alanine, L-tryptophan, D-tryptophan, DL-phenylalanine, L-phenylalanine, D-phenylalanine, D-tyrosine, and the like, and combinations thereof. [0035] DIAT form I also can be prepared, e.g., by crystallizing DIAT from an aqueous solution, e.g., water or a mixture of water and one or more polar organic solvents, and optionally isolating the resulting crystals. Suitable polar organic solvent can include, e.g., methanol, ethanol, acetonitrile, and combinations thereof. [0036] An exemplary process for preparing DIAT form I by crystallization includes: (i) refluxing a mixture of DIAT, water and, optionally, one or more polar organic solvents, preferably selected from the group consisting of methanol, ethanol, acetonitrile and combinations thereof;

(ii) allowing the mixture to cool sufficiently (preferably to about 25°C with stirring and then to about 5⁰C with further stirring), to precipitate crystals of DIAT form I;

(iii) optionally isolating the crystals, e.g., by filtration;

(iv) optionally washing the crystals; and

(v) optionally drying the crystals, e.g., at atmospheric pressure or under reduced pressure.

[0037] DIAT form II produces an X-ray powder diffraction pattern, e.g., as shown in Figure 7. A peak listing is provided in Table 2.

Table 2 DIAT form II - X-ray powder diffraction peak position and intensities

[0038] The strong diffraction peaks at 9.5, 16.1, 18.0, 26.2, 27.9, and the three peaks at 20.7, 21.1, 21.6 ±0.2 degrees 2Θ, are characteristic of DIAT form II. [0039] Alternatively, DIAT form II can produce a slightly different X-ray powder diffraction pattern, e.g., as depicted in Figure 8. A peak listing for the alternative X-ray powder diffraction pattern is provided in Table 3.

Table 3 DIAT form II - alternative X-ray powder diffraction peak position and intensities

[0040] A microscopic image of DIAT form II crystals is shown in Figure 2.

DIAT form II can exist as a hydrate containing about 5-15 % of water or about 1-3 equivalents of water. The water content in DIAT form II is typically less than the water content in DIAT form I.

[0041] In accordance with the present invention, DIAT form II can be produced by the drying/heating of DIAT form I. It has been found that the amount of water in DIAT form II can vary without any observable change in the crystalline structure. However, DIAT form II, which contains about 5% of water, may absorb water, e.g., from the environment, and transform into DIAT form I. Preferably, when DIAT form II is heated, no melting is observed, based on the weight loss curve observed in TGA, throughout the entire temperature range in which the hydrated form II exists. [0042] DIAT form II also can be produced by a process that includes crystallizing DIAT from a mixture of water and a suitable organic solvent, and optionally isolating the crystals. Suitable organic solvents can include, e.g., one or more organic solvents selected from the group consisting of isopropanol, ethyl acetate, and combinations thereof.

[0043] An exemplary process for preparing DIAT form II via crystallization includes:

(i) refluxing a mixture of DIAT, water and one or more organic solvents preferably selected from the group consisting of isopropanol, ethyl acetate, and combinations thereof;

(ii) allowing the mixture to cool sufficiently (preferably to about 25°C and then cooling to about 5°C while maintaining stirring) to precipitate crystals of DIAT form II;

(iii) isolating the crystals, e.g., by filtering a slurry of DIAT form II crystals thus produced;

(iv) optionally washing the crystals; and

[0044] In accordance with the present invention, DIAT form III can be produced by heating DIAT form II at temperatures above about 16O⁰C, at which DIAT form II can be substantially dried, to produce a phase transition from DIAT form II to substantially water-free (e.g., anhydrous) DIAT form III. Care should be taken when heating to convert DIAT form II into DIAT form III to avoid decomposition, which can occur at high temperatures. A characteristic DSC curve exhibited by DIAT form II is depicted in Figure 9. A characteristic TGA curve exhibited by DIAT form II depicted in Figure 10.

[0045] In some cases, water discharge in DIAT form II can begin at higher temperatures, e.g., as shown in the alternative TGA curve depicted in Figure 11. Both DSC and TGA curves may change due to changes in water content. The intensity of the second peak (onset 135-14O⁰C) can depend on the sample preparation, and can become much larger.

[0046] DIAT form III produces an X-ray powder diffraction pattern, e.g., as shown in Figure 12. A peak listing is provided in Table 4. Table 4 DIAT form III - X-ray powder diffraction peak position and intensities

[0047] The strong diffraction peaks at 14.8, 17.6, 19.3, 21.0, 21.8, 22.3, 25.4 and 25.6 ± 0.2 degrees 2Θ are characteristic of DIAT form III.

[0048] The DIAT form III is preferably anhydrous, e.g., containing less than about 0.3% water. The DIAT form III can be produced by substantially dehydrating

DIAT form II at temperatures of at least about 160⁰C (e.g., above about 160 ⁰C), although, as noted above, degradation has been observed above 16O⁰C in some cases.

For instance, melting and decomposition of crystalline DIAT form III has been observed at temperatures above about 19O⁰C.

[0049] A characteristic infrared spectrum exhibited by DIAT form III is depicted in Figure 13. The strong absorption peaks at 1614, 1121, 1061 and 847 ±4 cm^"1 are characteristic bands associated with DIAT form III.

[0050] A characteristic DSC curve of DIAT form III is depicted in Figure 14, and shows the melting peak at 191 ⁰C. A characteristic TGA curve of DIAT form III is depicted in Figure 15, and indicates that there is no weight loss from about room temperature to about 18O⁰C.

[0051] Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples, which are intended to be exemplary only.

[0052] The following procedures and methods were used in the examples.

[0053] DIAT crystalline forms I, II and III were characterized by powder X-ray diffraction, thereby generating fingerprint powder X-ray diffraction patterns for each particular crystalline form. Measurements of 2Θ values typically are accurate to within ± 0.2 degrees 2Θ. X-ray diffraction data were acquired using a PHILIPS X-ray diffractometer model PW1050-70. System description: KaI=I .54178 A, voltage

4OkV, current 28 mA, diversion slit = 1°, receiving slit = 0.2 mm, scattering slit = 1° with a Graphite monochromator. Experiment parameters: pattern measured between

2Θ = 4° and 2Θ = 30° with 0.05° increments; count time was 0.5 second per increment.

[0054] DIAT crystalline forms I₃ II and III of the present invention were further characterized by Fourier-transform infrared (FTIR) spectroscopy to an accuracy of ±

4 cm^"1 using a Nicolet Fourier-Transform Infrared spectrometer model Avatar 360, with Omnic software version 5.2. All samples were run using KBr pellets.

[0055] FTIR is a well-known spectroscopic analytical tool, which measures the absorption of IR energy by a sample from transitions in molecular vibrational energy levels. While FTIR is primarily used for identification of functional groups in a molecule, different polymorphic forms also can exhibit differences in FTIR.

[0056] DIAT crystalline forms I₃ II and III of the present invention also were characterized by differential scanning calorimetry (DSC), run on TA instruments model QlOOO, with Universal software version 3.88. Samples were analyzed inside crimped 40 μl Aluminum pans. Heating rate for all samples was 5 °C/min.

[0057] Differential scanning calorimetry (DSC) graphs were recorded using a

TA Instruments QlOOO Thermal Analyzer with Universal software (version 3.88).

Samples were analyzed inside crimped 40 μl Aluminum pans at a heating rate of 5

°C/min.

[0058] DIAT crystalline forms I₃ II and III of the present invention also were characterized by thermogravimetric analysis (TGA), a measure of the thermally induced weight loss of a material as a function of the applied temperature. Thermogravimetric analysis (TGA) was performed using a TA Instruments Q500

Thermal Analyzer with Universal Software (version 3.88). Samples were analyzed inside platinum baskets at a heating rate of 5°C/minute.

[0059] The water content measurements of DIAT crystalline forms I, II and III of the present invention were carried out using a Karl Fischer Titrator (Mettler Toledo

Model DL-53), according to standard procedures.

[0060] Microscopic images were taken using Olympus BX 50 (Light microscope equipped with C 4040 digital camera system), produced by Olympus

Optical Co. Ltd., Japan.

[0061] The DIAT starting material was prepared by resolving the racemic diamine as described in Schneider et al., J. Med. Chem., 30, 494-498 (1987).

EXAMPLE 1

[0062] This example demonstrates a method for preparing DIAT form I.

[0063] In a three-necked round-bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, DIAT (Ig) was dissolved in 6 ml ^"of 1% aqueous L- Alanine solution. The solution was heated using an oil bath to reflux, and allowed to cool to 25 ⁰C. The resulting large single crystals (0.90 g) were filtered and left to dry in a hood. Samples 2-9 were prepared according to the foregoing procedure with various modifications, as summarized in Table 5.

Table 5 Crystallization of DIAT form I from solutions containing different amino acids

EXAMPLE 2

[0064] This example demonstrates the preparation of DIAT form I. In a three- necked round-bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, DIAT (Ig) was mixed with methanol (10 ml). The mixture was heated to reflux and methanol was added in 4 ml portions until a solution was obtained (the total added volume was 80 ml). Refluxing was maintained while water was added (45 ml). The solution was allowed to cool to 25⁰C, and then stirred for 1 hour at that temperature. The solution was cooled to 5⁰C and stirring was continued at that temperature for additional 1 hour. The resulting suspension was filtered and washed with a cold mixture of water : methanol (1 :2 (vol./vol.)). The resulting crystals were dried at 6O⁰C under vacuum to afford DIAT Form I (0.83g).

EXAMPLE 3

[0065] This example demonstrates the preparation of DIAT form I. In a three- necked round-bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, DIAT (9.5 g) was mixed with water (89 ml). The solution was heated to reflux, then allowed to cool to room temperature and stirred at room temperature for 1 hour. The solution was cooled to 5⁰C, stirred at this temperature for additional 1 hour and filtered. The resulting cake was washed with cold water to obtain wet DIAT form I (9.1 g). EXAMPLE 4

[0066] This example demonstrates the preparation of DIAT form I. In a three- necked round-bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, DIAT (9.5 g) was mixed with 25 ml water. The solution was heated to reflux. Ethanol was added in several portions while refluxing (total volume of the added ethanol was 25 ml). The solution was allowed to cool to room temperature and stirred at room temperature for 1 hour. Then, the solution was cooled to 5⁰C, and stirring was maintained for additional 1 hour at 5⁰C, followed by filtration. The resulting cake was washed with cold mixture of water and ethanol (1:1 (vol./vol.)). The resulting crystals were dried under vacuum at 6O⁰C to afford DIAT form I (0.52 g)-

EXAMPLE 5

[0067] This example demonstrates the preparation of DIAT form I. DIAT form

I was prepared according to the procedure of Example 13, except that acetonitrile was used instead of ethanol, to afford 1.04 g of dry DIAT form I.

EXAMPLE 6

[0068] This example demonstrates the preparation of DIAT form II. In a three- necked round-bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, DIAT (1 g) was mixed with water (30 ml). The solution was heated to reflux and isopropanol was added in several portions while refluxing (total volume of the added isopropanol was 30 ml). The solution was cooled to 25⁰C, stirred at that temperature for 1 hour, then cooled to 5⁰C and stirred for 1 hour at that temperature. The resulting slurry was filtered and the cake was washed with cold 1 : 1 water:isopropanol. The resulting solid was dried at 6O⁰C under vacuum to obtain DIAT form II (0.8 g). EXAMPLE 7

[0069] This example demonstrates the preparation of DIAT form II. In a three- necked round-bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, DIAT (1 g) was mixed with water (30 ml). The solution was heated to reflux and ethyl acetate was added in several portions while refluxing (total volume of the added ethyl acetate was 30 ml). The two-phase mixture was cooled to 25⁰C, stirred at that temperature for 1 hour, then cooled to 5⁰C and stirred at that temperature for 1 hour. The resulting slurry was filtered and the solid thereby obtained was washed with cold ethyl acetate. The resulting solid was dried at 6O⁰C under vacuum to obtain DIAT form II (0.83 g).

EXAMPLE 8

[0070] This example demonstrates the preparation of DIAT form II. DIAT form I (Ig) was dried at 80⁰C under vacuum for 2 hours, to produce DIAT form II. The resulting material contained 5% water (by TGA).

EXAMPLE 9

[0071] This example demonstrates the preparation of DIAT form III. DIAT form II (1 g) was heated for 10 minutes at 160 ⁰C, to produce DIAT form III.

[0072] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0073] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0074] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:

1. A crystalline solid selected from the group consisting of (S)-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate form I, (5)-2,6-diamino- 4,5,6,7-tetrahydrobenzothiazole monotartrate form II, (S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate form III, and mixtures thereof.

2. The crystalline solid of claim 1, which is (S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate form I.

3. The crystalline solid of claim 2, wherein the X-ray powder diffraction pattern of the crystalline solid exhibits peaks at 7.8, 9.3, 13.2, 14.4, 15.7, 17.1, 25.8, and 26.9 ± 0.2 degrees 2Θ.

4. The crystalline solid of claim 2, wherein the infrared spectrum of the crystalline solid exhibits absorption peaks at 1652, 1317 and 978 cm^"1, a broad band at 1500-1600 cm^"1, and a doublet at about 800-850 cm^"1.

5. The crystalline solid of claim 2, wherein DSC curve of the crystalline solid exhibits peaks with onsets at about 12O⁰C, about 135-14O⁰C and about 195-200 ⁰C.

6. The crystalline solid of claim 2, wherein the water content of the crystalline solid is about 15 ± 2%.

7. A method for preparing the crystalline solid of claim 2, comprising crystallizing (5)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate from an aqueous solution comprising about 1% of one or more amino acids, to produce large single crystals of (5)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate form I.

8. The method of claim 7, comprising:

(i) refiuxing an aqueous solution comprising (S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate and about 1% of one or more amino acids,

(ii) allowing the solution to cool sufficiently to produce crystals of (5)-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate form I;

(iii) optionally isolating the crystals; and

(iv) optionally drying the crystals.

9. The method of claim 8, wherein the one or more amino acids is selected from the group consisting of natural amino acids, synthetic amino acids, and combinations thereof.

10. The method of claim 8, wherein the one or more amino acids is selected from the group consisting of L-amino acids, D-amino acids, DL-amino acids, and combinations thereof.

11. The method of claim 8, wherein the one or more amino acids is selected from the group consisting of L-alanine, L-tyrosine, D-alanine, L-tryptophan, D-tryptophan, DL-phenylalanine, L-phenylalanine, D-phenylalanine, D-tyrosine, and combinations thereof.

12. A method for preparing the crystalline solid of claim 2, comprising crystallizing (5)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate from an aqueous solution, and optionally isolating the crystals.

13. The method of claim 12, wherein the aqueous solution comprises water and one or more polar organic solvents.

14. The method of claim 13, wherein the aqueous solution comprises one or more polar organic solvents selected from the group consisting of methanol, ethanol, acetonitrile, and combinations thereof.

15.' The method of claim 12, comprising:

(i) refluxing a mixture of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate, water and, optionally, one or more polar organic solvents;

(ii) allowing the mixture to cool sufficiently to precipitate crystals of (S)- 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate form I;

(iii) optionally isolating the crystals;

(iv) optionally washing the crystals; and

(v) optionally drying the crystals.

16. The crystalline solid of claim 1, which is (5)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate form II.

17. The crystalline solid of claim 16, wherein the X-ray powder diffraction pattern of the crystalline solid exhibits peaks at 9.5, 16.1, 18.0, 26.2, 27.9, 20.7, 21.1, and 21.6 ± 0.2 degrees 2Θ.

18. The crystalline solid of claim 16, wherein the DSC curve of the crystalline solid exhibits peaks with onsets at about 120⁰C, about 135-14O⁰C and about 195-200 ⁰C.

19. A method for preparing the crystalline solid of claim 16, comprising crystallizing (5)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate from an aqueous solution comprising water and an one or more organic solvents selected from the group consisting of isopropanol, ethyl acetate, and combinations thereof, and optionally isolating the crystals.

20. The method of claim 19, comprising:

(i) refluxing (5)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate in the aqueous solution; (ii) allowing the mixture to cool sufficiently to produce crystals of (S}-2,6- diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate form II; (iii) optionally isolating the crystals; (iv) optionally washing the crystals; and (v) optionally drying the crystals.

21. A method for preparing the crystalline solid of claim 16, comprising heating (£)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate form I at temperature of at least about 8O⁰C, optionally under reduced pressure, to produce (S)- 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate form II.

22. The crystalline solid of claim 1, which is (S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate form III.

23. The crystalline solid of claim 22, wherein the X-ray powder diffraction pattern of the crystalline solid exhibits peaks at 14.8, 17.6, 19.3, 21.0, 21.8, 22.3, 25.4, and 25.6 ± 0.2 degrees 2Θ.

24. The crystalline solid of claim 22, wherein the infrared spectrum of the crystalline solid exhibits absorption peaks at 1614, 1121, 1061 and 847 ± 4 cm^'1 .

25. The crystalline solid of claim 22, wherein the water content of the crystalline solid is less than about 0.3%.

26. A method for preparing the crystalline solid of claim 23, comprising heating (iS)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate form II at a temperature of at least 160⁰C, to produce (5)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate form III.

27. A method of preparing pramipexole, comprising converting the (S)- 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole monotartrate of claim 1 into pramipexole.

28. The method of claim 27, comprising alkylating the (S)-2,6-diamino- 4,5,6,7-tetrahydrobenzothiazole monotartrate, to produce pramipexole.

29. The method of claim 29, comprising acylating the (5)-2,6-diamino- 4,5,6,7-tetrahydrobenzothiazole monotartrate to produce (5)-2-amino-4,5,6,7- tetrahydro-6-(propionamido)benzothiazole, reducing the amide to produce pramipexole, and optionally forming a salt thereof.

30. The method of claim 27, wherein the (S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate is form I.

31. The method of claim 27, wherein the (S)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate is form II.

32. The method of claim 27, wherein the (5)-2,6-diamino-4,5,6,7- tetrahydrobenzothiazole monotartrate is form III.