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Process for preparing N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]- 4-pyrimidinyl)-N’-propylsulfamide and intermediates thereof

IP.com Disclosure Number: IPCOM000234588D
Publication Date: 2014-Jan-21

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Process for preparing N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]- 4-pyrimidinyl)-N'-propylsulfamide and intermediates thereof

    N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl)-N'- propylsulfamide referred herein as Compound I has the following Chemical structure:

Provided herein are processes for preparing Compound I and intermediates thereof.

Lithium N-propylsulfamide

Example 1: Process for preparing lithium N-propylsulfamide

    N-propylsulfamide (69.1 g, 0.5mol) was dissolved at RT in MTBE (600 ml).The insoluble part was removed by filtration (0.25 g white powder). Water (0.3 ml) was added to the solution. Lithium amide (11.48 g) was added in portions at 15-20 °C. The mixture was stirred overnight at RT. The salt was collected by filtration, washed with MTBE (200ml +100 ml) and dried at 40 °C, 100 mbar overnight to obtain lithium N-propylsulfamide (64.03 g).

1H-NMR (DMSO-d6) δ 0.82 (t, J=7.5 Hz,3H), 1.39 (m, 2H), 2.71 (t, J= 7.5 Hz, 2H), 3.34 (br,

2H); 13C-NMR (DMSO-d6) δ 11.9, 22.8, 45.4.

Figure 1: X-ray powder diffraction (XRPD) pattern of lithium N-propylsulfamide

Intensity (counts)

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    According to figure 1, the crystalline form of lithium N-propylsulfamide is characterized by XRPD peaks at: 5.9, 11.8, 17.7, 18.8, 20.7, 21.4, 22.3, 23.6, 25.4, 27.0, 29.1,


29.4, 29.7, 31.4, 32.2, 34.0, 35.8, 36.4 and 39.1 degrees two theta ±0.2 degrees two theta.

Sodium N-propylsulfamide

Example 2: Process for preparing Sodium N-propylsulfamide

    N-Propylsulfamide (13.82 g, 100 mM) was dissolved in 2-propanol (140 ml). While stirring and cooling under nitrogen at room temperature, sodium hydroxide (4.2 g, 105 mM) was added to the solution, and the mixture was stirred at room temperature for 2 h and at 0 - 10 °C for 30 min. The mixture was diluted with THF (20 ml), the precipitated solid was collected by filtration, washed with THF (2 x 20 ml) and dried in reduced pressure at 35 °C to yield Sodium N-propylsulfamide (14.91 g); MS (ES) [M+H]+= 161.039; 1H-NMR (DMSO-d6) δ 0.84 (t, J=7.5 Hz,3H), 1.40 (m, 2H), 2.73 (t, J= 7.5 Hz, 2H), 3.09 (br, 2H).

Figure 2: XRPD pattern of sodium N-propylsulfamide

    According to figure 2, the crystalline form of sodium N-propylsulfamide is characterized by XRPD peaks at: 5.3, 5.6, 6.3, 11.1, 12.7, 16.2, 16.6, 18.7, 19.8, 21.1, 21.4,


21.9, 22.2, 23.3, 24.3, 24.7, 25.4, 27.2, 27.9, 28.2, 29.4, 31.9, 33.4 and 34.3 degrees two theta ±0.2 degrees two theta.


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Figure 3: FTIR of sodium N-propylsulfamide

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N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylsulfamide

Example 3: Process for preparing N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-

propylsulfamide

    5-(4-Bromophenyl)-4,6-dichloropyrimidine (3.04 g, 10 mM) was dissolved in DMSO (20 ml) while stirring at room temperature...