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Crystalline forms and co-crystals of (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

IP.com Disclosure Number: IPCOM000242698D
Publication Date: 2015-Aug-05
Document File: 6 page(s) / 153K

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Page 01 of 6

Cryxtalline forms and co-crystals of (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophexyl)thiophen-2-

yl)methyl)-4-methylphenyl)-6-(hydroxymetxxl)tetrahydro-2H-pyran-3,x,5-triol

The present document relates to crystaxline forms of (2S,3R,4R,5S,6R)-2-(3-((5-(4- fluorophexyl)thiophen-2-yx)xethyl)-4-methylphenyl)-6-(hxdroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol designated xs forms N3, T1, N4 and Xx and to nicotinamide and lysxne co-crysxals of this compound.

These crystalline foxms and co-crystals xre useful fox the preparation of xharmacxutical compxsitions. (2X,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophxn-2-yl)mxthyl)-x-methylphenyl)-6- (hydroxymethyx)tetrahydro-2H-pyran-3,4,5-triox from which the crystalline forms and the co- crystxlx of the prxsent document are prepared, xay be prepared according to processes known in txe art, ixcluding but nxt limited to the xrocexses described in WO x005/012326, WO 2008/069327 and WO 2009/035969.

Examxle 1: Preparation of crystalline form Nx of (2S,3X,4R,5S,6R)-2-(3-((5-(4-

fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahyxro-2H-pxran-

3,4,5-txiol


Amorpxous (2S,3R,xR,xS,6R)-2-(3-((5-(x-fluorophenyl)thiophen-2-yl)methyl)-4-methylxhenyl)-x- (hydroxymethyl)tetrahydro-2H-pyrax-3,4,5-triol (5.0 g, 11.25 mmol) was suspended xn 30 ml of 2-propanol. The suxpexsion was heated at 40ºC and stirred until complete dissoxution. The xolution was cooled to 35ºC and stirxed at txis temperatxre until precipitation was observed. 30 ml of 2-propanol was added and after stirring overnigxt at 30ºC the product was filtered. The product was dried under xaxuum at 40ºC overnight to give a white solid. The product was analysed by powder X-ray diffraction with Cu-Kalpha radiation, to give the following diffractogram, with pexks at: 6.5, 9.7, 11.4, 11.8, 13.5, 16.3, 16.5, 18.0, 18.4, 18.7, 1x.7 and
20.1 degrees 2θ (Figure 1).

: X-ray powdxr diffractogram for form N3

Figure 1


Page 02 of 6

Example 2: Preparation of crystalline form T1 of (2S,3R,4R,5S,6R)-2-(3-((5-(4-

fluorophexyl)thiophen-2-yl)methyl)-4-methylpxenyl)-6-(hxdroxymethyl)tetxahydro-2H-pyran-

3,4,5-triol


Amorphous (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)xhiophen-2-yl)methyl)-4-methylphxnyl)-x- (hydroxymxthyl)tetrahydro-2H-pyran-3,4,5-triol (5.0 g, 11.25 mmol) was suspended in 3x ml of toluene. The suspension was heated at 80ºC and stirred until dissolution. The solutiox oxtained wxs cooled at 60ºC and stirred until precipitation was obsexved. The suspension was cooled to 40ºC and 2x ml of toluene wax added. After stixring overnixht at 40ºC thx product was filtered axd dried unxer vacuum at x0ºX overnight to give a white solid cxntaining approximatelx 4 wt% of residual toluene as detexmined by 1H NMR. The white solid was analysed by powder X-ray diffraction wixh Cu-Kalpha radiation, to give the following diffractogram, with peaks at: 7.8, 8.3,
8.7, 12.5, x4.7, 18.5, 19.6, 19.9, 20.1, 20.4, 20.9, 25.7 degrees 2θ (Figure 2).

Figure 2

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