WO 2015129603, NEW PATENT, Daiichi Sankyo Co Ltd, Edoxaban

WO 2015129603

HIGH-PURITY CRYSTALS OF ACTIVE BLOOD COAGULATION FACTOR X (FXA) INHIBITOR

DAIICHI SANKYO COMPANY,LIMITED [JP/JP]; 3-5-1,Nihonbashi Honcho,Chuo-ku, Tokyo 1038426 (JP)

Claims highly pure crystalline form of edoxaban p-toluenesulfonate monohydrate. Useful for treating thrombotic diseases. Daiichi Sankyo had developed and launched edoxaban for treating non-valvular atrial fibrillation, deep vein thrombosis and pulmonary embolism, the drug was recently launched in US (in February 2015) and approved in Europe (in June 2015).

The present invention addresses the problem of providing high-purity crystals of a compound which is represented by formula (1a) and is an active blood coagulation factor X (FXa) inhibitor. High-purity crystals of a compound represented by formula (1a) which: are characterised by being obtained by a step for dissolving crystals in a solvent and thereafter performing recrystallisation; have a 0.03% or less maximum content of one impurity as the impurity content by percentage; and have a 0.13% or less total impurity content.

It shows the inhibitory effect of activated blood coagulation factor X (FXa), a compound useful as a prophylactic and / or therapeutic agent for thrombotic diseases, the following formula (1a)[Formula 1]

In N represented ¹ - (5-Chloro-2-yl) -N ² - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - {[(5-methyl-4 , 5,6,7-tetrahydro thiazolone [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) Etanjiamido p- toluenesulfonic acid monohydrate [hereinafter, may be referred to as compound (1a) is there

　(Reference Example 1) N ¹ - (5-Chloro-2-yl) -N ² - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - {[(5-methyl - 4,5,6,7 Synthesis of tetrahydro thiazolone [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) Etanjiamido p- toluenesulfonic acid monohydrate (1a) (WO 07 / the method described in 032 498 pamphlet)　Was prepared by the method described in WO 07/032498 pamphlet, N ¹ - (5-Chloro-2-yl) -N ² - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - the {[(5-methyl-4,5,6,7-tetra-hydro thiazolopyridine [5,4-c] pyridine-2-yl) carbonyl] amino} cyclohexyl) Etanjiamido (86.8g), at 60 ℃, it was dissolved in 30% aqueous ethanol (418ml), p- 30% aqueous ethanol solution of toluene sulfonic acid monohydrate (29.0g) a (167ml) was added. The reaction mixture, after stirring for 1 hour at 70 ℃, was gradually cooled to room temperature, ethanol was added, and the mixture was stirred for 16 hours. The reaction solution under ice-cooling, after stirring for 1 hour, The crystals were collected by filtration to give the title compound 102.9g.

　The resulting compound, the absorption peak of the same intensity at the same wave number standard and the (known compound) was observed in the IR.
The obtained compound, in analysis using HPLC, as impurities, a peak of more impurities (both 0.03 wt%) is confirmed, the total of the impurities was 0.16 wt.% Since, its purity was 99.84% (Note that the content of% refers to% of the HPLC area value of the free form of formula (1a) compound).

¹ H-NMR (DMSO-d6) delta: 1.45-1.54 (1H, M), 1.66-1.78 (3H, M), 2.03-2.10 (2H, M), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3 .13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m) , 7.11 (2H, d, J = 7.8Hz), 7.46 (2H, d, J = 8.2Hz), 8.01 (2H, d, J = 1.8Hz), 8.46 ( 1H, t, J = 1.8Hz), 8.75 (1H, d, J = 6.9Hz), 9.10-9.28 (1H, br.s), 10.18 (1H, br.s ), 10.29 (1H, s).

Elemental analysis: Anal. Calcd. For: C; 50.43%, H; 5.46%, N; 13.28%.
Found: C; 50.25%, H; 5.36%, N; 13.32%

/////////////WO 2015129603, NEW PATENT, Daiichi Sankyo Co Ltd, Edoxaban