Crystalline form of Eltrombopag free acid

Abstract

The present invention relates to crystalline form of Eltrombopag free acid and its process for preparation. ##STR00001##

Claims

1. A process for the preparation of crystalline Eltrombopag Form H1 having 2 angle positions at about 6.3, 7.0, 9.0, 11.5, 12.7, 14.2, 20.5, 23.1, 25.5 and 28.60.2 degrees, which comprises: a) dissolving Eltrombopag in dimethyl formamide; b) heating the solution to reflux at 50-100 C.; c) cooling the solution to below 35 C. and adding an alcoholic solvent selected from methanol, ethanol, n-butanol, and isopropanol; d) heating the solution to reflux at 50-100 C. and e) isolating the crystalline Eltrombopag Form H1.

2. A process for the preparation of crystalline Form 1 of Eltrombopag Olamine, which comprises: a) preparing crystalline Eltrombopag Form H1 according to the method of claim 1 and dissolving said crystalline Eltrombopag Form H1 in tetrahydrofuran; b) optionally treating with Carbon; c) adding an alcoholic solution of 2-amino alcohol and ethanol; d) removing the solvents; and e) isolating crystalline Eltrombopag Olamine salt Form I.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a X-ray powder diffraction spectrum of crystalline Eltrombopag Form H1 obtained as per Example 1.

(2) FIG. 2 is a X-ray powder diffraction spectrum of crystalline Eltrombopag Form H1 obtained as per Example 2.

(3) FIG. 3 is a X-ray powder diffraction spectrum of crystalline Eltrombopag Olamine salt Form I obtained as per Example 3.

POWDER X-RAY DIFFRACTION METHOD

(4) X-ray powder diffraction spectrum was measured on a broker axs D8 advance X-ray powder diffractometer having a copper-K radiation. Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees two theta per step and a step time of 10.8 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

(5) In the following section embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilled in the art.

Comparative Example: Preparation of Crystalline Eltrombopag Form I

a. Preparation of 5-bromo-2-nitrophenol

(6) 3-Bromophenol (32.9 g, 0.19 mol) was added slowly to a cold (10 C.) solution of sodium nitrate (29.0 g, 0.34 mol) in conc. sulfuric acid; (40.0 g) and water (70.0 mL) and the resulting mixture was allowed to stir at room to temperature for 2 h. Water (200 mL) was added and the resulting mixture was extracted with diethyl ether and the extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to afford first the title compound (8.1 g, 20%), Mp 40-42 C., then the undesired isomer, 3-bromo-4-nitrophenol, as a yellow solid (12.7 g, 31%). Mp=125-127 C.

b. Preparation of 3-Hydroxy-4-nitrobiphenyl-4-carboxylic acid

(7) A solution of the compound from comparative Example a (2.18 g, 0.01 mol.), 4-carboxyphenylboronic acid; (1.74 g, 0.0105 mol.), 2M aqueous sodium carbonate (10.0 mL; 0.02 mol.) and tetrakistriphenylphosphino palladium (0.5 g) in 1,4-dioxane (60.0 mL) was stirred and heated under reflux under a nitrogen atmosphere for 24 h,

(8) The reaction mixture was cooled and evaporated and the residue treated with 6M aqueous hydrochloric acid; (100 mL). The grey precipitate was filtered and washed well with water then diethyl ether to afford the title compound (2.3 g; 88%) as a colorless solid.

c. Preparation of 4-Amino-3-hydroxybiphenyl-4-carboxylic acid Hydrochloride Salt

(9) A solution of the compound from comparative Example b (1.6 g, 0.0062 mol.) in ethanol (75.0 mL), water (50.0 mL) and 3M aqueous sodium hydroxide (2.0 mL, 0.0062 mol.) was hydrogenated over 10% palladium on carbon (0.2 g) at room temperature and 50 psi for 2 h.

(10) The reaction mixture was filtered, treated with 3M aqueous hydrochloric acid; (25.0 mL) then evaporated and the residue triturated with little water to afford the title compound (1.18 g; 72%) as a brown solid.

d. Preparation of 1-(3,4-Dimethylphenyl)-3-methyl-3-pyrazolin-5-one

(11) A solution of 3,4-dimethylphenylhydrazine hydrochloride (17.7 g; 0.1 mol.), ethyl acetoacetate (13.0 g; 0.1 mol.) and sodium acetate (8.2 g; 0.1 mol.) in glacial acetic acid; (250 mL) was stirred and heated under reflux for 24 h. The mixture was cooled and evaporated and the residue dissolved in diethyl ether (1 L) and carefully washed with saturated aqueous sodium hydrogen carbonate (5200 mL). The ethereal layer was evaporated to afford the title compound (15.4 g; 76%).

e. Preparation of Eltrombopag

(12) A suspension of the compound from comparative Example c (1.0 g; 0.0044 mol.) in 1M aqueous hydrochloric acid; (15.0 mL) was cooled to 5 C. then treated dropwise with a solution of sodium nitrite (0.32 g; 0.0046 mol.) in water (5.0 mL). The yellow mixture was stirred at 5 C. for a further 10 min. then treated in one portion with the compound from comparative Example d (0.882 g, 0.0044 mol.) followed by the portion-wise addition of sodium hydrogen carbonate (1.8 g; 0.022 mol.) and ethanol (20.0 mL) ensuring the final pH of the reaction mixture is approximately 7-8. The red solution was then stirred at room temperature for 24 h.

(13) The mixture was filtered to give a red solid which was slurried in water (50.0 mL) and then acidified with concentrated hydrochloric acid. Filtration afforded the title compound (0.68 g; 35%) as an orange powder, Mp=280 C.

f. Preparation of Crystalline Eltrombopag Form I

(14) Crude Eltrombopag (50 g) was suspended in 800 ml of glacial acetic acid in reactor. The suspension was stirred for five hours under reflux and cooled to 40 C. Crystals formed were filtrated off, washed with 200 ml of methanol:water (1:1) and dried at 60 C. yielding 40 gm orange solid of crystalline Eltrombopag Form I.

EXAMPLES

Example 1

(15) Preparation of Crystalline Eltrombopag Form H1

(16) Eltrombopag (15 g) was added to dimethylformamide (300 ml) in a reactor. The contents were heated to reflux at 75 C. for 75 minutes and then slowly cooled to 35 C. To the obtained solution, methanol was added and heated to reflux for 75 minutes and the contents were cooled slowly to obtain a solid mass. The obtained product mass was filtered and dried to yield crystalline Eltrombopag Form H1.

(17) Yield: 13 g

(18) Chromatographic Purity: 99.66% (by HPLC)

(19) PXRD: As shown in FIG. 1.

Example 2

(20) Preparation of Crystalline Eltrombopag Form H1

(21) Eltrombopag (13.5 Kg) was added to dimethylformamide (165 L) in a reactor. The contents were heated to reflux at 75 C. for 75 minutes and then slowly cooled to 35 C. To the obtained solution, methanol (220 L) was added and heated to reflux for 75 minutes and the contents were cooled slowly and then washed with methanol (60 L). The obtained product mass was filtered and dried to yield crystalline Eltrombopag Form H1.

(22) Yield: 12 Kg

(23) Chromatographic Purity: 99.76% (by HPLC)

(24) PXRD: As shown in FIG. 2.

Example 3

(25) Preparation of Crystalline Eltrombopag Olamine Salt Form I

(26) Crystalline Eltrombopag Form H1 (15 Kg) was added to tetrahydrofuran (135 L) in a reactor. 2-amino alcohol dissolved in ethanol (165 L) was added to the above solution and stirred. After completion of the reaction, the solvent was distilled partially, thereafter cooled to 31 C. and stirred for 5 hrs. The obtained product was filtered, washed with ethanol and dried to yield Eltrombopag olamine salt Form I.

(27) Yield: 13 Kg

(28) Chromatographic Purity: 99.2% (by HPLC)

(29) PXRD: As shown in FIG. 3.