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Crystalline form of ethyl-5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazole-2-butanoate and salts thereof

IP.com Disclosure Number: IPCOM000193314D
Publication Date: 2010-Feb-18
Document File: 8 page(s) / 185K

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The IP.com Prior Art Database

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Crystalline form of ethyl-5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazole- 2-butanoate and salts thereof

Ethyl-5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazole-2-butanoate (referred as "BBOH") having the following formula;

COOCH2CH3

N

N

N

OH

    and salts thereof are intermediates of the synthesis of 5-[bis(2- chloroethyl)amino]-1-methyl-1H-benzimidazole-2-butanoic acid hydrochloride (referred as "BNT HCl") having the following;

O

Cl

OH

HCl

N

N

N

Cl

    which belongs to the family of drugs called alkylating agents. BNT HCl is the substance in the treatment of leukemia, chronic lymphocytic leukemia (CLL) and also being studied for the treatment of sarcoma.

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    A crystalline form of BBOH and salts thereof were found and are described herein below.

BBOH crystalline form
The crystalline form of BBOH, described herein has diffraction peaks at about
8.2, 11.2, 12.2, 12.9, 16.5, 16.8, 21.2, 21.8, 23.5 and 23.8 ± 0.2 degrees two-theta.

In addition above crystalline form can be further characterized by XRPD pattern

and peak list described on Figure 1 and Table 1.

Figure 1: A powder XRD pattern of crystalline BBOH

400

Intensity (cps)

300

200

100

0

5 10 15 20 25 30 35

2Theta (°)

Table 1: A powder XRD peaks list of crystalline BBOH

 Peak Position

[°2Th.]

Relative Intensity

[%]
8.19 42.8
8.97 2.6
10.26 0.4
11.23 6.1
11.67 13.3
11.82 5.0
12.20 8.5

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12.95 12.8
14.46 7.3
14.59 5.3
15.88 21.2
16.01 23.4
16.46 23.6
16.79 23.2
17.31 4.7
17.70 8.0
18.03 15.6
18.57 35.5
18.84 100.0
19.18 13.9
19.55 28.8
20.59 20.9
21.29 42.5
21.84 45.3
22.23 22.2
22.52 37.9
22.75 7.0
23.13 8.1
23.51 93.4
23.82 89.3
24.26 21.2
24.58 4.5
24.79 1.6
25.34 10.7
26.00 2.7
26.49 8.7
27.01 10.8
27.56 33.9
27.82 9.5
28.15 5.9
28.68 16.0
29.44 9.0
29.90 1.5
30.30 4.5
31.00 1.7
31.62 11.9
32.04 4.9
32.46 5.7
32.92 3.3
33.97 5.0
34.28 4.5
35.06 6.0
35.60 2.3
36.18 4.6
36.60 0.7

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37.17 1.9
38.16 2.0
38.67 8.8

BBOH fumarate crystalline form

    The crystalline form of BBOH fumarate, described herein has diffraction peaks at about 6.5, 9.5, 12.8, 17.1, 19.0, 23.0, 24.9, 26.0, 26.4 and 28.5 ± 0.2 degrees two-theta.

    In addition above crystalline form can be further characterized by XRPD pattern and peak list described on Figure 2 and Table 2.

Figure 2: A powder XRD pattern of crystalline BBOH fumarate

Intensity (cps)

500

400

300

200

100

0

5 10 15 20 25 30 35

2Theta (°)

Table 2: A powder XRD peaks list of crystalline BBOH fumarate

 Peak Position

[°2Th.]

Relative Intensity

[%]
6.55 22.3
9.47 4.6
10.98 0.4
11.44 1.9
12.78 17.5
13.68 0.9

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14.11 1.0
15.03 6.2
15.77 6.5
16.56 3.4
17.14 16.1
17.77 10.5
19.00 62.7
19.77 4.6
20.43 14.0
20.58 9.7
20.94 11.7
21.99 1.0
22.26 1.8
22.73 5.4
23.02 18.2
23.71 22.8
24.05 23.3
24.92 100.0
26.04 50.9
26.45 54.1
27.42 4.1
27.81 5.6
28.09 10.3
28.48 16.1
29.31 9.7
29.75 0.6
30.22 6.4
30.44 3.8
31.88 4.7
32.31 4.5
33.14 9.8
33.52 9.5
34.01 2.1
34.45 2.3
35.06 1.4
35.44 2.7
35.90 2.7
36.49 1.3
37.40 8.6
37.75 12...