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Crystalline Forms of Ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-n-(pyridin-2-yl)-1h-benzo[d]imidazole-5-carboxamido)propanoate Hydrochloride andPreparation Thereof

IP.com Disclosure Number: IPCOM000214414D
Publication Date: 2012-Jan-26
Document File: 8 page(s) / 115K

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Crystalline Forms of Ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-n- (pyridin-2-yl)-1h-benzo[d]imidazole-5-carboxamido)propanoate Hydrochloride and

Preparation Thereof

    Provided hereinafter are crystalline forms of ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5- carboxamido)propanoate hydrochloride, referred to herein as Compound 1.

Crystalline form I

Intensity(counts)

40000

22500

10000

2500

5 10 15 20 25 30 35 2Theta (°)

Main peaks: 7.7, 9.7, 12.6, 15.4, 17.2, 20.2, 21.5, 22.3, 25.5 and 26.5 degrees two theta 0.2 degrees two theta.

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Crystalline form II

Intensity(counts)

14400

10000

6400

3600

5 10 15 20 25 30 35 2Theta (°)

Main peaks: 8.7, 13.5, 16.2, 17.5, 19.2, 19.9, 20.3, 21.8, 22.3 and 24.1 degrees two theta 0.2 degrees two theta.

Crystalline form III

Intensity(counts)

32400

25600

19600

14400

10000

6400

3600

5 10 15 20 25 30 35 2Theta (°)

Main peaks: 7.0, 8.6, 11.8, 14.1, 14.4, 18.8, 21.0, 23.1, 24.8 and 26.3 degrees two theta 0.2 degrees two theta.

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Crystalline form IV

Intensity(counts)

19600

14400

10000

6400

5 10 15 20 25 30 35 2Theta (°)

Main peaks: 5.4, 9.0, 10.7, 11.8, 17.1, 18.2, 19.7, 20.5, 23.2, 27.3 degrees two theta 0.2 degrees two theta.

PXRD method

    Samples after being powdered in a mortar and pestle are applied directly on silicon plate holder. The X-ray powder diffraction pattern was measured with Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.54184 ( ngström), X'Celerator (2.022º 2Q) detector. Scanning parameters: angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuous scan.

Examples

Example 1

Step 1: preparation of crude Compound 1

    Ethanol (500 mL) was charged into reactor at 25-30 C. ethyl 3-(2-((4- cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5- carboxamido)propanoate (referred to as Compound 2) (250 g) was added at 25-30 C with

stirring. The reaction mixture was cooled to 0-5 °C. HCl gas (3,63 kg) was purged for 5 h while maintaining the temperature at 22-47 °C. After getting the desired conversion, HCl gas purging

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was stopped, the reaction solution was cooled down to 0-10 °C and N2 gas was bubbled though reaction mass at 0-10 °C for 1-2 h to remove the excess of HCl gas. Ethanol (5 L) was charged into the remaining mixture under N2 atmosphere at 0-10 °C and stirred for 20-30 min at 0-10 °C until clear solution was obtained. The solution was cooled down to -10 °C to 0 °C and 17M NH3/EtOH (18-28%, 750 mL) was added slowly at -5 °C to 20 °C until pH maintained 8-10. The temperature was raised to 30-35 °C, and the reaction mixture was stirred for 4-18 h and filtered at 30-35 °C. The wet cake was washed with ethanol (500 mL) and the filtrate was charged in the reactor and distilled under vacuum at 45-55 °C until 1,25 L of solution was remained in the reactor. The solution was heated to 70-78 °C and 2-propan...