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Crystalline forms of N-(2-(4-(4-fluorobenzylcarbamoyl) -5-hydroxy-1- methyl-6-oxo-1, 6-dihydropyrimidin-2-yl)propan-2-yl) -5-methyl-1,3,4- oxadiazole-2- carboxamide intermediates

IP.com Disclosure Number: IPCOM000234569D
Publication Date: 2014-Jan-19
Document File: 6 page(s) / 60K

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  Crystalline forms of N-(2-(4-(4-fluorobenzylcarbamoyl) -5-hydroxy-1- methyl-6-oxo-1, 6-dihydropyrimidin-2-yl)propan-2-yl) -5-methyl-1,3,4-

oxadiazole-2- carboxamide intermediates

    N-(2-(4-(4-fluorobenzylcarbamoyl) -5-hydroxy-1-methyl-6-oxo-1, 6- dihydropyrimidin-2-yl)propan-2-yl) -5-methyl-1,3,4-oxadiazole-2- carboxamide potassium salt referred to as Compound I, has the following chemical structure:

O

OK

F

N

   N N

O

  HN O

HN

N

O

    Benzyl 2-(4-(4-fluorobenzylcarbamoyl)-1, 6-dihydro-5-hydroxy-1-methyl-6- oxopyrimidin-2-yl) propan-2-ylcarbamate referred to as Compound II is an intermediate in the preparation of Compound I.

    Samples of Compound II were prepared by the process described in examples 1-3, and were analyzed by X-ray powder diffraction ("XRPD") to provide a crystalline form. Figure 1 presents the XRPD of the obtained form.

Figure 1: XRPD of crystalline Compound II

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    According to figure 1, the crystalline form of Compound II is characterized by XRPD peaks at: 7.6, 9.7, 12.7, 19.4, 20.5, 25.5, 26.9, 29.2, 30.1 and 32.5 degrees two-theta ± 0.2 degrees two-theta.

    5-Methyl-1,3,4-oxadiazole-2-carboxylic acid potassium salt, referred to as Compound III, is another intermediate in the preparation of Compound I

    Crystalline form of Compound III was obtained by the processes described in examples 4 and 5. Figure 2 presents the XRPD of the obtained form.

Figure 2: XRPD of crystalline Compound III

    According to figure 2, the crystalline form of Compound III is characterized by XRPD peaks at: 6.9, 13.5, 16.6, 20.3, 25.4, 27.1, 28.2, 34.1, 35.1 and 36.9 degrees two-theta ± 0.2 degrees two-theta.

    X-ray powder diffraction was obtained by using ARL (SCINTAG) powder X- Ray diffractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.5418 Å was used. Scanning parameters: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05°, and a rate of 3 deg. 2 theta/min.

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Preparation of the starting material: {1-[4-(4-Fluoro-benzylcarbamoyl)-5,6- dihydroxy-pyrimidin-2-yl]-1-methyl-ethyl}-carbamic Acid Phenethyl Ester

    2-(1-Benzyloxycarbonylamino-1-methyl-ethyl)-5,6-dihydroxy- pyrimidine-4- carboxylic acid methyl ester (1.0 kg) was charged into methanol (2.5 l) at 20-30 ºC. Triethyl amine (0.34 kg) was added at 20-30ºC, over at least 30 minutes to obtain a reaction mass. The obtained reaction mass was heated up to 55-60ºC and stirred for 15-20 minutes.4-Fluorobenzyl amine (0.42 kg) was added at 55-65ºC, over at least 30 minutes. The reaction mass was heated at reflux (60-70ºC) and the progress of the reaction monitored by HPLC (not more than 2.0% of 2-(1-Benzyloxycarbonylamino-1-methyl- ethyl)-5,6-dihydroxy- pyrimidine-4-carboxylic acid methyl ester was obtained). Acetic acid (0.33 kg) was added at 60-70ºC, over at least 30 minutes. Hot water (6 l, 60-70ºC) was added at 60-70ºC, over at least 30 minutes. The reaction mass was stirred at 60-70ºC for 60-70 minutes, then it was co...