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Crystalline forms of (Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide hydrochloride

IP.com Disclosure Number: IPCOM000240716D
Publication Date: 2015-Feb-20
Document File: 7 page(s) / 322K

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Crystalline forms of (Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3- ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide hydrochloride

Herein is described the preparation of different polymorphic forms of (Z)-N-(2- (diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide hydrochloride, forms I to IV and forms VI to VII. Their corresponding X-Ray diffractograms are presented.

Preparation of Form I


(Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide (1g) was suspended in isopropanol (30mL) at room temperature. Concentrated hydrochloric acid (3eq) was added. The suspension was heated to 70ºC for 10 min and cooled to 20/25ºC. The solid was filtrated and washed with isopropanol (2x 1mL). The solid was dried under vacuum at 50ºC to yield (Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2- oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide hydrochloride form I (97%

Figure 1: Powder XRD diffractogram of crystalline form I

Peak Number

1 6.07 14.54 2431 100.0 2 9.45 9.35 284 11.7 3 9.60 9.20 617 25.4 4 11.95 7.40 288 11.8 5 12.15 7.28 311 12.8 6 12.65 6.99 255 10.5 7 13.04 6.78 169 7.0
8 14.53 6.09 226 9.3
9 15.05 5.88 771 31.7 10 16.43 5.39 646 26.6

yield) as an orange solid.

Pos. [°2Th.]

d-spacing
[Å]

Height [cts]

Rel. Int. [%]



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Peak Number

Pos. [°2Th.]

d-spacing
[Å]

Height [cts]

Rel. Int. [%]

11 17.52 5.06 166 6.8 12 18.12 4.89 197 8.1 13 18.27 4.85 133 5.5 14 18.33 4.84 152 6.3 15 18.95 4.68 367 15.1 16 20.68 4.29 303 12.5 17 23.03 3.86 562 23.1 18 25.93 3.43 1900 78.2 19 26.36 3.38 1598 65.7

Preparation of Form II


(Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide hydrochloride form III (2g) with the following XRD were suspended in

dimethylformamide (16mL) and heated to 86ºC to clear solution.

Counts

5817_JE-92277-01.xrdml

7000

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4000

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0

10

30

40

20 Position [º2Theta](Copper(Cu))

Figure 2: Powder XRD diffractogram of crystalline form III

Peak Number

Pos. [°2Th.]

d-spacing
[Å]

Height [cts]

Rel. Int. [%]

1 4.58 19.27 7440 100.0 2 9.01 9.81 1241 16.7 3 9.19 9.62 2600 34.9 4 13.80 6.41 313 4.2
5 15.24 5.81 905 12.2 6 16.65 5.32 642 8.6
7 16.93 5.23 1296 17.4 8 18.33 4.84 833 11.2


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Peak Number

Pos. [°2Th.]

d-spacing
[Å]

Height [cts]

Rel. Int. [%]

9 18.63 4.76 714 9.6 10 18.90 4.69 430 5.8 11 19.15 4.63 707 9.5 12 20.43 4.34 672 9.0 13 25.98 3.43 2136 28.7

Then, the solution was cooled to 40ºC and ethyl acetate (16mL) was added. The suspension was cooled to 20ºC, filtered and washed with ethyl acetate (2x4mL). The solid was dried under vacuum and (Z)-N-(2-(diethylamino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide hydrochloride form II (1g, 50% yield) was obtained as a yellow to orange solid.

Figure 3: Powder XRD diffractogram of crystalline form II

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