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CRYSTALLINE FORMS OF L-TARTRATE SALT OF (2R)-4-OXO-4-[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-a]PYRAZIN-7(8H)-YL]-1-(2,4,5-TRIFLUOROPHENYL)BUTAN-2-AMINE

IP.com Disclosure Number: IPCOM000237887D
Publication Date: 2014-Jul-18
Document File: 8 page(s) / 151K

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The IP.com Prior Art Database

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CRYSTALLINE FORMS OF L-TARTRATE SALT OF (2R)-4-OXO-4-[3- (TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-a]PYRAZIN-7(8H)-YL]-1-(2,4,5- TRIFLUOROPHENYL)BUTAN-2-AMINE

The present document relates to crystalline forms of L-tartrate salt of (2R)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan- 2-amine designated as forms B, C, D, E and F. These crystalline forms are useful for the preparation of pharmaceutical compositions

Example 1 Preparation of crystalline form B of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-

dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan-2-amine L-tartrate

(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan-2-amine (5.0 g, 12.3 mmols), L-tartaric acid (1.84 g, 12.3 mmols), isopropanol (14 mL) and water (14 mL) were charged to a 50 mL reactor with mechanical overhead stirrer and heated to 70 ºC until dissolution, then cooled to ambient temperature and stirred for about 16 hours. The product was filtered and washed with isopropanol (2 × 10 mL). The product was dried at 70 ºC under vacuum for 20 hours. Yield 6.11 g (87%). The product was analysed by powder X-ray diffraction, see Figure 1 and Table 1 below.

Figure 1

: X-ray powder diffractogram for form B


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Peak Number Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]

1
5,91

14,93 9,3

2

8,37

10,56 6,6

3

9,81

9,01 24,3

4

11,86

7,45 4,5

5

13,11

6,75 32,6

6

14,26

6,20 100,0

7

15,58

5,68 64,9

8

15,97

5,54 39,7

9

16,77

5,28 24,9

10

17,03

5,20 26,4

11

17,49

5,07 35,4

12

17,61

5,03 18,8

13

17,80

4,98 17,0

14

18,24

4,86 48,0

15

19,02

4,66 38,0

16

19,52

4,54 34,1

17

19,78

4,49 9,1

18

20,99

4,23 23,1

19

21,68

4,10 14,2

20

22,13

4,01 7,1

21

22,93

3,88 9,8

22

23,85

3,73 36,6

23

24,37

3,65 5,5

24

24,62

3,61 5,7

25

24,83

3,58 5,1

26

25,28

3,52 22,2

27

25,87

3,44 6,9

28

26,21

3,40 59,9

29

26,51

3,36 6,2

30

27,42

3,25 11,6

31

27,65

3,22 4,7

32

27,93

3,19 16,7

33

28,02

3,18 15,0

34

30,61

2,92 5,9

35

32,98

2,71 11,5

36

37,61

2,39 10,5

37

37,82

2,38 15,8

38

2,33 12,1

Table 1: X-Ray powder diffraction peak listing for form B

Example 2 Preparation of crystalline form C of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-

38,60

dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan-2-amine L-tartrate

(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan-2-amine L-tartrate (1.0 g) and 20 mL of methanol were charged to a 50 mL reactor with mechanical overhead stirrer. The mixture was heated to 60 ºC until dissolution and then cooled to ambient temperature and stirredfor about 16 hours. The product was filtered and dried at 70 ºC under vacuum for 16 hours. Yield 0.496 g (50%). The product was analysed by powder X-ray diffraction, see Figure 2 and Table 2 below.


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Figure 2

: X-ray powder diffractogram for form C

Peak Number

Pos. [°2Th.]

d-sp...