Process for preparing purine derivatives

Abstract

The present invention relates to a process for preparing a compound of formula [I], said process comprising the steps of: formula [II]+formula [III].fwdarw.formula [I] (i) forming a reaction mixture comprising (a) a compound of formula [II], (b) a compound of formula [III] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof, and optionally (d) a base; (ii) heating said reaction mixture to a temperature of at least about 150 C. to form a compound of formula [I]; (iii) isolating said compound of formula [I]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R.sup.1 and R.sup.2 are each independently H, alkyl or haloalkyl; R.sup.3 and R.sup.4 are each independently H, alkyl, haloalkyl or aryl; R.sup.5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R.sup.6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and formula (A) where one of X, Y and Z is N and the remainder are CR.sup.9; R.sup.7, R.sup.8 and each R.sup.9 are independently H, alkyl or haloalkyl, wherein at least one of R.sup.7, R.sup.8 and R.sup.9 is other than H. Further aspects of the invention relate to a highly diastereoselective process for the preparation of compounds of formula [III], a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I], and to a process for preparing the crystalline tartrate salt and free base of compounds of formula [I]. ##STR00001##

Claims

1. A process for preparing a compound of formula [I], ##STR00027## wherein: R.sup.1 and R.sup.2 are each independently H, alkyl or haloalkyl; R.sup.3 and R.sup.4 are each independently H, alkyl, haloalkyl or aryl; R.sup.5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R.sup.6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and ##STR00028## where one of X, Y and Z is N and the remainder are CR.sup.9; R.sup.7, R.sup.8 and each R.sup.9 are independently H, alkyl or haloalkyl, wherein at least one of R.sup.7, R.sup.8 and R.sup.9 is other than H; said process comprising the steps of: (i) forming a reaction mixture comprising (a) a compound of formula [II], (b) a compound of formula [III] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof; (ii) heating said reaction mixture to a temperature of at least about 150 C. to form a compound of formula [I]; and (iii) isolating said compound of formula [I].

2. A process according to claim 1 wherein the reaction mixture in step (i) further comprises a base.

3. A process according to claim 1 wherein the reaction mixture comprises from about 2 to about 3 mole equivalents of compound [III] relative to compound [II].

4. A process according to claim 1 wherein step (iii) comprises extracting the reaction mixture from step (ii) into water and ethyl acetate, separating the ethyl acetate phase and drying with a drying agent, filtering and concentrating the filtrate.

5. A process according to claim 1 which comprises converting said compound of formula [I] into the L-tartrate salt.

6. A process according claim 1 which comprises the steps of: ##STR00029## (i) forming a reaction mixture comprising (a) a compound of formula [2], (b) a compound of formula [3] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof; (ii) heating said reaction mixture to a temperature of at least about 150 C. to form a compound of formula [1]; and (iii) isolating said compound of formula [1].

7. A process according to claim 6 wherein the reaction mixture in step (i) further comprises a base selected from N,N-diisopropylethylamine (DIEA), tri-.sup.Npropylamine, and tri-.sup.Nbutylamine.

8. A process according to claim 6 wherein compound [2] has a purity of at least 97%.

9. A process according to claim 6 wherein compound [3] has a diastereomeric excess of at least 85%.

10. A process according to claim 1 wherein compound [III] is prepared by the steps of: ##STR00030## (a) treating a compound [V] with (S)-2-Me-CBS-oxazoborolidine and borane-N,N-diethylaniline complex in a solvent comprising THF to form a compound [IV]; and (b) removing the protecting group PG from said compound [IV] to give compound [III], wherein PG is a protecting group, preferably Boc, R.sup.1 is alkyl or haloalkyl, and R.sup.3 is alkyl, haloalkyl or aryl.

11. A process according to claim 10 which comprises the steps of: ##STR00031## (a) treating a compound [5] with (S)-2-Me-CBS-oxazoborolidine and borane-N,N-diethylaniline complex in a solvent comprising THF to form a compound [4]; and (b) removing the protecting group PG from said compound [4] to give compound [3], where PG is a protecting group, preferably Boc.

12. A process according to claim 1 which comprises preparing a compound of formula [II] by the steps of: ##STR00032## (i) treating a compound of formula [VI] with HF, pyridine and tBuONO to form a compound of formula [VII]; and (ii) treating said compound of formula [VII] with R.sup.5Br in DMSO and K.sub.2CO.sub.3 to form a compound of formula [II]; where R.sup.5 and R.sup.6 are as defined in claim 1.

13. A process according to claim 12 which comprises the steps of: ##STR00033## (i) treating compound [6] with HF, pyridine and .sup.tBuONO to form compound [7]; and (ii) treating said compound [7] with isopropyl bromide in DMSO and K.sub.2CO.sub.3 to form compound [2].

14. A process for preparing the crystalline L-tartrate salt of compound [1], said process comprising the steps of refluxing a solution of compound [1] in ethanol and adding dropwise thereto a solution of L-tartaric acid in a mixture of water and ethanol, wherein the ratio of ethanol:water in the final mixture after addition of the L-tartaric acid solution is at least about 15:1 ##STR00034##

Description

(1) The present invention is further described with reference to the following figures, wherein:

(2) FIG. 1 shows the reaction scheme for preparing compound [1] as disclosed in WO 2008/122767.

(3) FIG. 2 shows the reaction scheme for preparing compound [1]-L-tartrate as disclosed in WO 2011/089401.

(4) The present invention is further described with reference to the following non-limiting Examples.

EXAMPLES

Abbreviations

(5) THF tetrahydrofuran

(6) EtOAc ethyl acetate

(7) PMA phosphomolybdic acid

(8) MeOH methanol

(9) DCM dichloromethane

(10) TBME tertiary butyl methyl ether

(11) DCM dichloromethane

(12) DIEA N,N-diisopropylethylamine

(13) .sup.1H NMR: .sup.1H NMR spectra were collected using a JEOL ECX 400 MHz spectrometer equipped with an auto-sampler. The samples were dissolved in D.sub.6-DMSO for analysis and the spectrum was acquired at ambient temperature using a standard proton experiment acquiring 16 scans using Delta NMR Processing and Control Software version 4.3. The data were then processed using ACD labs 1D NMR processor version 12.0.

(14) DSC: DSC data were collected on a PerkinElmer Pyris 6000 DSC equipped with a 45 position sample holder. The instrument was verified for energy and temperature calibration using certified indium. A predefined amount of the sample, 0.5-3.0 mg, was placed in a pin holed aluminium pan and heated at 20 C..Math.min.sup.1 from 30 to 350 C., or varied as experimentation dictated. A purge of dry nitrogen at 20 ml.Math.min.sup.1 was maintained over the sample. The instrument control, data acquisition and analysis were performed with Pyris Software v 11.1.1 Revision H.

(15) XRPD: X-Ray Powder Diffraction patterns were collected on a PANalytical diffractometer using Cu K radiation (45 kV, 40 mA), - goniometer, focusing mirror, divergence slit (), soller slits at both incident and divergent beam (4 mm) and a PIXcel detector. The software used for data collection was XPert Data Collector, version 2.2f and the data was presented using XPert Data Viewer, version 1.2d.

(16) XRPD patterns were acquired under ambient conditions via a transmission foil sample stage (polyimide-Kapton, 12.7 m thickness film) under ambient conditions using a PANalytical XPert PRO. The data collection range was 2.994-35028 with a continuous scan speed of 0.202004s.sup.1.

(17) HPLC: Method A

(18) Sample Solution Preparation:

(19) Accurately weigh 50 mg of sample into a 100 ml volumetric flask. Add 50 ml of Methanol to the flask, dissolve via sonication if necessary, dilute to volume with Purified Water and mix the resulting solution thoroughly. Column: 1504.6 mm Luna C18 (2), 5 m particle size, (ex-Phenomenex; #OOF-4252-EO) Mobile Phase: A0.01 M Ammonium Acetate Buffer (pH 8.0) BAcetonitrile Flow Rate: 1.0 ml.Math.min.sup.1 Injection Volume: 5 l Detection: UV@ 254 nm Column Temp: 30 C. Post Run: 5 minutes

(20) HPLC: Method B

(21) Sample Solution Preparation:

(22) Accurately weigh 50 mg of sample into a 100 ml volumetric flask. Add 50 ml of Methanol to the flask, dissolve via sonication if necessary, dilute to volume with Purified Water and mix the resulting solution thoroughly. Column: 1504.6 mm XBridge Phenyl, 3.5 m particle size, (ex-Waters; #186003335) Mobile Phase: APurified Water: Trifluoroacetic acid (100:0.1) BAcetonitrile: Trifluoroacetic acid (100:0.1) Flow Rate: 1.0 ml.Math.min.sup.1 Injection Volume: 5 l Detection: UV@ 268 nm Column Temp: 30 C. Post Run: 5 minutes

(23) Chiral HPLC Column: 2504.6 mm Chiralpak AD-H, 5 m particle size, (ex-Daicel Chemical Industries, Ltd; #DAIC 19325) Mobile Phase: Ethanol:Hexane (50:50) Flow Rate: 1.0 ml.Math.min.sup.1 Injection Volume: 20 l Detection: UV@ 268 nm Column Temp: 40 C. Run Time: 20 minutes

(24) HRGC:

(25) Sample Solution Preparation

(26) Accurately weigh 50 mg of sample into a 10 ml volumetric flask. Dissolve in 5 ml of dichloromethane, using sonication if required, dilute to volume with dichoromethane and mix the resulting solution thoroughly. Column: DB-1 30 m0.32 mm; 1.0 m film thickness (ex-J&W Scientific #123-1033) Oven Program: 40 C. (Hold 5 mins) then 10 C..Math.min.sup.1 to 300 C. (Hold 10 mins) Injector Temperature: 200 C., split Column Temperature: 250 C., F.I.D. Head Pressure: 12 psi, constant pressure Carrier Gas: Nitrogen Spilt Ratio: 50:1 Injection Volume: 2 l Liner: SGE Focusliner with glass wool insert

(27) Enantiomeric Excess by HRGC:

(28) Standard Solution Preparation

(29) Accurately weigh 10 mg of each enantiomer [(2R,3S); (2S,3R); (2R,3R); (2S,3S)] into a suitable container. Dissolve in about 1 ml of HPLC grade dichloromethane, sonicating if necessary. Add 500 l of trifluoroacetic anhydride and 500 l of trifluoroacetic acid and allow to derivatise for 15-30 minutes at room temperature. Inject this solution.

(30) Sample Solution Preparation

(31) Accurately weigh, in duplicate, 10 mg of sample into a suitable container. Dissolve in about 1 ml of HPLC grade dichloromethane, sonicating if necessary. Add 500 l of trifluoroacetic anhydride and 500 l of trifluoroacetic acid and allow to derivatise for 15-30 minutes at room temperature. Inject this solution. Column: Gamma-TA Cyclodextrin 30 m0.32 mm; 0.125 m film (ex-Astec; Cat no. 73033) Oven Program: 80 C. (Hold 10 mins) then 2 C..Math.min.sup.1 to 90 C. (Hold 20 mins) then 10 C..Math.min.sup.1 to 80 C. Injector Temperature: 200 C., split Column Temperature: 250 C., F.I.D. Head Pressure: 20 psi, constant pressure Carrier Gas: Nitrogen Spilt Ratio: 50:1 Injection Volume: 1 l Liner: SGE Focusliner with glass wool insert

(32) $\%\mathrm{enantiomeric}\mathrm{excess}=\frac{\mathrm{Peak}\mathrm{area}\mathrm{of}\left[\left(2R,3S\right)-\left(2S,3R\right)\right]}{\mathrm{Peak}\mathrm{area}\mathrm{of}\left[\left(2R,3S\right)+\left(2S,3R\right)\right]}100\%$$\%\mathrm{diastereomeric}\mathrm{excess}=\frac{\mathrm{Peak}\mathrm{area}\mathrm{of}\left[\left(2R,3S\right)-\left(2S,3S\right)\right]}{\mathrm{Peak}\mathrm{area}\mathrm{of}\left[\left(2R,3S\right)+\left(2S,3S\right)\right]}100\%$

(2R,3S)-3-aminopentan-2-ol Synthesis

(33) Preparation of Compound [4]

(34) ##STR00020##

(35) (S)-2-Methyl-CBS-oxaborolidine (1M solution in toluene, 59.6 mL, 0.06 mol) was diluted with THF (171 mL) in a dry, nitrogen purged vessel. Borane N,N-diethylaniline complex (102 mL, 0.57 mol) was added dropwise at room temperature and the solution was allowed to stir for 15 minutes. Compound [5] (115.0 g, 0.57 mol) was dissolved in THF (345 mL) and added dropwise over 4.5 h. After the addition was complete the reaction was allowed to stir overnight at room temperature under a nitrogen atmosphere. Thin layer chromatography (20% EtOAc in heptane, visualised by PMA) indicated the complete consumption of starting material. The reaction was carefully quenched via dropwise addition of methanol (174 mL) over 1 h. The temperature was maintained at <20 C. throughout the quench. The solution was concentrated in vacuo before additional methanol (174 mL) was added. The solution was concentrated under reduced pressure to afford a white waxy solid. The crude product was recrystallised from heptane (202 mL). The recrystallised product was filtered and rinsed with heptane (2156 mL) to yield a white solid. This was dried in a vacuum oven at 40 C. overnight to give compound [4] as a white solid (99.2 g, 85%). Analysis was by HRGC and chiral HRGC as described above.

(36) Deprotection of Compound [4]

(37) ##STR00021##

(38) MeOH (645 mL) was gassed with HCl for 1 hour at <20 C. in a 20 L flask under N.sub.2. The solution was 3.85M by titration. The flask was cooled to <15 C. Compound [4] (101.1 g, 0.50 mol) was charged portion-wise at <15 C. The solution was stirred overnight. The reaction was complete by TLC (5% MeOH/DCM, visualised with PMA). The solution was concentrated in vacuo at 35-40 C. The oil was azeotroped with EtOAc (475 mL) and triturated to give a white solid. The solid was taken up in EtOAc (588 mL). The reaction mixture was cooled to 0-5 C. and sparged with NH.sub.3 (g) for 1 hour at 0-5 C. under N.sub.2. At the end of the addition the pH was 8. The mixture was filtered and the filter cake was washed with EtOAc (147 mL). The filtrate was concentrated in vacuo at 35-40 C. to give the desired product [3] as a light yellow oil (50.7 g). .sup.1H NMR confirmed the identity of the product and indicated 4% residual EtOAc to be present giving an active yield of 48.7 g, 95%.

(39) Preparation of Compound [7]

(40) ##STR00022##

(41) 60% HF/pyridine (2982.3. g) was charged to a 6 L PTFE vessel and cooled to between 35 and 30 C. Compound [6] (322.2 g, 1 mol eq) was charged to the vessel maintaining the batch temperature between 35 and 30 C. The vessel contents were allowed to warm to between 15 and 10 C., then tert-butyl nitrite (160 ml, 1 mol eq) was added dropwise maintaining the temperature between 15 and 5 C. The batch was allowed to warm to room temperature (between 15 and 20 C.) and stirred for 17 hours. The batch was sampled for completion by HPLC which indicated the presence of 11.3% compound [6]. Additional tert-butyl nitrite (48 ml, 0.3 mol eq) was added and stirred for 3 hours, a completion check showed 2.3% compound [6] remaining. Additional tert-butyl nitrite was added (48 ml, 0.3 mol eq) and stirred overnight. A final completion indicated 0.7% compound [6] remained. The reaction mixture was quenched into sat.aq. K.sub.2CO.sub.3 (12000 ml), additional sat.aq. K.sub.2CO.sub.3 (3500 ml) was added to adjust to pH 8, the batch was stirred for 90 minutes then filtered. The filter was washed with purified water (3200 ml). The solid was returned to the quench vessel and slurried in purified water (3200 ml) for 34 minutes and filtered. The filter was washed with purified water (3200 ml). The solid was returned to the quench vessel and slurried in purified water (3200 ml) for 34 minutes and filtered. The filter was washed with purified water (3200 ml) and TBME (31600 ml). The solid was dried at 45 C. under vacuum. Yield=222.5 g (68.3%); purity 94.9% by HPLC (Method A).

(42) Preparation of Compound [2]

(43) ##STR00023##

(44) The reaction was carried out in one batch which was split into four portions for the workup and then purified in two portions achieving an overall yield of 2261.6 g (79% vs target 85%).

(45) Under N.sub.2 was charged DMSO (25000 ml), compound [7] (2479.9 g 1 mol eq) and potassium carbonate (2504.7 g 2 mol eq). 2-bromopropane (8520 ml 10 mol eq) was added maintaining the batch temperature between 15 and 25 C. The reaction mixture was heated to 60 C. and stirred for 35 minutes maintaining the temperature between 58 and 62 C. The reaction mixture was sampled for completion analysis. HPLC (Method A) indicated the reaction was complete, (0.14% compound [7] remaining). The reaction mixture was cooled to between 18 and 25 C. The batch was split into 4 approximately equal portions. Each portion was returned to the vessel with purified water (11200 ml) and ethyl acetate (11200 ml), stirred for 10 minutes and the layers separated.

(46) Reaction Work-Up

(47) The aqueous layer was charged to the vessel and extracted with ethyl acetate (36200 ml). The combined organic layers were charged to the vessel and washed with purified water (69300 ml). The organic layer was dried over magnesium sulphate (1014.1 g) and filtered. The filter cake was washed with ethyl acetate (32500 ml). The batch solution was sampled for HPLC analysis which indicated a crude purity of 94.1%.

(48) Purification

(49) The dried organic layers were combined into two portions. Each portion was distilled from the 50 L vessel until minimum stir and then transferred to a 2 L rotary evaporator to complete the concentration. The crude compound [2] (1480.5 g) was dissolved in 15% MeOH/EtOAc (3000 ml) in a carboy. Silica (2961.3 g) was charged to the carboy and the contents were agitated over 15 minutes. Further 15% MeOH/EtOAc (2000 ml) was charged to the carboy to help slurry the silica. A plate filter was set up and packed with silica (4441.5 g) in 15% MeOH/EtOAc. The crude compound [2]/silica slurry was transferred to the filter plate and packed. The silica pad was then washed with 15% MeOH/EtOAc (88800 ml) collected in 5 fractions, 15% MeOH/EtOAc (44360 ml) collected in 2 fractions and 15% MeOH/EtOAc (44360 ml) collected in 2 fractions. Fractions containing compound [2] were polish filtered and concentrated. The resulting solid was azeotroped with EtOAc (33000 ml) and dried in a vacuum oven overnight at 30 C. Yield=1090.3 g; purity 96.9% by HPLC (Method A).

(50) The corresponding alkenyl analogue of compound [2] can be prepared as follows. A suspension of compound [7] (1.0 g) and phosphorus pentoxide (1.04 g, 2 eq) in toluene (40 ml), collidine (0.9 g, 2 eq) and acetone (2.1 g, 10 eq) was heated at reflux with stirring overnight. The reaction was cooled to room temperature and filtered. The filter cake was stirred with sat. aq. NaHCO.sub.3 (30 ml) and toluene (30 ml) for 5 minutes and then refiltered. The phases were separated and the aqueous was extracted with toluene (30 ml). The combined organics were dried (sodium sulfate) filtered and concentrated in vacuo. The product was purified by chromatography (silica 65 g) eluent=EtOAc.fwdarw.10% MeOH in EtOAc) to afford 190 mg of product 90% pure by .sup.1H NMR and a further 0.1 g of less pure material. The less pure product was recolumned (silica 51 g, eluent=4% MeOH in DCM) to give additional product (70 mg). Total yield 260 mg (22.7%). The alkenyl analogue of [2] can be reacted with compound [3] (3-10 eq) in PEG200 and DIPEA by heating overnight at 120-130 C. The product can be purified by column chromatography using 4% MeOH in DCM as eluent to give the product in >95 purity by .sup.1H NMR.

(51) Purification of Compound [2]

(52) ##STR00024##

(53) In order to assess the effect of higher purity compound [2] on the final coupling reaction profile, 55 g of compound [2] (96.80% purity by HPLC) was passed through a silica pad eluting with 15% MeOH in DCM. The resulting product was then slurried in diethyl ether, filtered and dried to give 49.3 g of compound [2] with a purity of 98.46% by HPLC (Method A).

(54) Preparation of Compound [1] Using 1,2-Propanediol in Step (i)

(55) ##STR00025##

(56) A solution of compound [2] (36.2 g, 115.15 mmol) and compound [3] (24.7 g, 23.8 g active, 230.71 mmol) in 1,2-propanediol (181 mL) was heated at 150 C. overnight. Analysis by HPLC (Method B) indicated 0.29% propanediol adduct, 95.01% compound [1] and 0.57% compound [4]. Alternatively, PEG-200 can be used instead of 1,2-propanediol. Optionally the reaction mixture further comprises DIEA (2 mole equivalents). After cooling to 15-20 C., water (250 mL) and ethyl acetate (120 mL) were charged to the vessel and the batch was stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (4100 mL). The combined organic layers were washed with 2.5 w/w % brine (3160 mL) then water (3160 mL). The organic layer was dried over MgSO.sub.4 and filtered. The filtrate was concentrated then azeotroped with TBME (2250 mL) to isolate the crude compound [1] free base (46.9 g). HPLC analysis indicated a purity of 95.22% (Method B).

(57) The crude material (46.9 g) was taken up in TBME (94 mL) and heated at reflux. A seed of crystalline compound [1] (0.009 g; prepared in accordance with the teachings of WO 2011/089401; Form A; Cyclacel Limited) was added and the resulting hazy solution was cooled to 50-55 C. and stirred for 30 minutes. The seed crystal was prepared in accordance with Example 1 of WO 2011/089401 (Cyclacel Limited). The reaction mixture was then allowed to cool to room temperature overnight. The resulting solid was filtered, washed with TBME (347 mL) and pulled dry. The off-white solid was dried at 40 C. under vacuum to give crystalline compound [1] free base (36.0 g, 79%; Form A). XRPD and DSC characterisation was in accordance with Form A, WO 2011/089401; see Table 1 for reference XRPD peaks). Optionally, the secondary hydroxyl group of compound [1] can be oxidised by treating with an oxidising agent, such as pyridium chlorochromate (0.2 equiv) and periodic acid (2.5 equiv) in MeCN as solvent, e.g. stirring at room temperature for 21 h, and then recharging with further pyridinium chlorochromate and periodic acid as necessary in order to drive the reaction to completion (followed by purification using column chromatography).

(58) Preparation of Compound [1] Using PEG-200 and DIEA in Step (i)

(59) A small scale reaction reaction was run to compare HPLC reaction profiles of a reaction using PEG-200 in direct comparison to 1,2-propanediol. Thus, under N.sub.2 was charged compound [2] (1.0 g, 3.181 mmol) and the reaction solvent (9.0 mL, 9 volumes). The mixture was then stirred for 5 minutes before the addition of the DIEA (2.2 mL, 4 eq) and compound [3] (0.66 g, 6.362 mol), the reactions were then heated to temperature (150 C.). The reaction profile are shown after 72 h are shown in the table below.

(60) TABLE-US-00002 Compound [1] Compound [2] Largest Single Impurity Solvent HPLC area % HPLC area % HPLC area % 1,2-Propanediol 89.55% 0.16% Single impurities 3.25% PEG-200 87.66% 2.33% Single impurities 3.60%

(61) Synthesis of Compound [1]-L-Tartrate Salt

(62) ##STR00026##

(63) Crystalline compound [1] free base (29.9 g, 75.22 mmol) was dissolved in ethanol (420 mL) and the resulting solution heated at reflux. A solution of L-tartaric acid (11.29 g, 75.22 mmol) in water (12 mL)/ethanol (30 mL) was added dropwise maintaining the batch temperature at 75-78 C. The solution was polish filtered (cooled to 57 C. during filtration with no evidence of crystallisation). The filtered solution was warmed to 60-65 C. and seeded with compound [1]-L-tartrate salt form II (0.003 g) prepared in accordance with Example 5 of WO 2011/089401 (Cyclacel Limited). The mixture was stirred at 60-65 C. for 1 hour during which time crystallisation initiated. The suspension was then cooled to 15-20 C. at 10 C./h. After stirring at 15-20 C. for 1 hour, the solid was filtered, washed with ethanol (360 mL) and pulled dry. Further drying in a vacuum oven yielded [1]-L-tartrate salt as a white solid (36.0 g, 87% from free base). .sup.1H NMR confirmed the identity of the product and HPLC (Method B) indicated a purity of 98.80%. The product was also analysed by chiral HPLC. DSC analysis (peak 182.73 C., onset 179.61 C.) and XRPD confirmed form II in accordance with WO 2011/089401 (see Table 2 for reference XRPD peaks).

(64) Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

(65) TABLE-US-00003 TABLE 1 XRPD peaks for crystalline free base (Form A) of compound [1] Pos. Height FWHM d-spacing Rel. Int. Tip width [2Th.] [cts] [2Th.] [] [%] [2Th.] 7.5313 21162.64 0.0768 11.73852 100.00 0.0921 9.6026 846.92 0.0768 9.21066 4.00 0.0921 10.2275 400.15 0.1023 8.64925 1.89 0.1228 11.2954 1863.94 0.1023 7.83384 8.81 0.1228 11.6652 300.53 0.1023 7.58631 1.42 0.1228 12.2672 3812.02 0.1023 7.21534 18.01 0.1228 12.6242 497.83 0.1023 7.01205 2.35 0.1228 13.1780 953.85 0.1023 6.71859 4.51 0.1228 14.0653 4092.77 0.1023 6.29672 19.34 0.1228 14.8535 1458.15 0.0768 5.96431 6.89 0.0921 15.1515 343.64 0.0768 5.84765 1.62 0.0921 15.5775 2894.50 0.1279 5.68868 13.68 0.1535 16.9914 2108.17 0.1023 5.21838 9.96 0.1228 17.6862 1501.97 0.1279 5.01490 7.10 0.1535 18.3040 644.51 0.0591 4.84701 3.05 0.0709 18.3954 1212.49 0.0768 4.82314 5.73 0.0921 18.6301 1666.18 0.1023 4.76289 7.87 0.1228 18.9784 1639.81 0.1279 4.67626 7.75 0.1535 19.3292 475.31 0.1023 4.59219 2.25 0.1228 20.2061 1067.39 0.1023 4.39483 5.04 0.1228

(66) TABLE-US-00004 TABLE 2 XRPD peaks for L-tartrate salt (Form E, also known as Form II) of compound [1] Height FWHM Tip width Pos. [2Th.] [cts] [2Th.] d-spacing [] Rel. Int. [%] [2Th.] 6.6675 15483.76 0.0768 13.25733 100.00 0.0921 8.2340 241.15 0.1023 10.73824 1.56 0.1228 9.7722 479.22 0.1023 9.05118 3.09 0.1228 11.9598 926.89 0.1023 7.40005 5.99 0.1228 12.3792 494.24 0.0768 7.15029 3.19 0.0921 13.0632 4104.92 0.0768 6.77739 26.51 0.0921 13.3777 2386.00 0.1023 6.61876 15.41 0.1228 13.9359 413.30 0.0768 6.35490 2.67 0.0921 14.9035 1349.55 0.1023 5.94439 8.72 0.1228 15.4032 975.17 0.0768 5.75266 6.30 0.0921 15.9507 949.23 0.1023 5.55642 6.13 0.1228 16.2665 488.77 0.1023 5.44926 3.16 0.1228 16.5423 792.08 0.1023 5.35902 5.12 0.1228 17.3614 2687.54 0.1023 5.10799 17.36 0.1228 17.5690 1410.91 0.1023 5.04809 9.11 0.1228 17.8630 201.26 0.1023 4.96566 1.30 0.1228 19.6395 1756.56 0.0768 4.52032 11.34 0.0921 19.8636 777.97 0.0768 4.46982 5.02 0.0921 20.1195 549.42 0.1023 4.41355 3.55 0.1228 20.7288 1423.91 0.1279 4.28518 9.20 0.1535 21.1373 389.18 0.1279 4.20327 2.51 0.1535 21.5804 674.89 0.1535 4.11797 4.36 0.1842 22.5683 459.02 0.1535 3.93989 2.96 0.1842 22.9541 780.05 0.1279 3.87454 5.04 0.1535 23.2869 904.34 0.1023 3.81992 5.84 0.1228 23.5693 1652.40 0.1535 3.77478 10.67 0.1842 24.0730 899.56 0.1535 3.69692 5.81 0.1842 24.6316 316.32 0.1791 3.61434 2.04 0.2149 25.2971 1357.36 0.1535 3.52074 8.77 0.1842 26.3772 346.67 0.1023 3.37898 2.24 0.1228 27.0905 141.69 0.1023 3.29160 0.92 0.1228 27.6723 474.86 0.1023 3.22371 3.07 0.1228 27.9727 708.87 0.1535 3.18977 4.58 0.1842 28.9051 262.52 0.1535 3.08896 1.70 0.1842 29.2843 136.18 0.1535 3.04982 0.88 0.1842 30.0801 73.71 0.1535 2.97092 0.48 0.1842 30.4059 137.17 0.1279 2.93982 0.89 0.1535 31.9006 27.79 0.1535 2.80541 0.18 0.1842 34.4898 70.18 0.2047 2.60050 0.45 0.2456