Pemetrexed synthesis

Yield:137281-23-3 95%

Reaction Conditions:

Stage #1:pemetrexed diethyl ester p-toluenesulfonic acid salt with sodium hydroxide in water at 5 - 15; for 2 h;
Stage #2: with hydrogenchloride in ethanol;water; pH=3 at 5 - 50; for 1 h;

Steps:

2 Preparation of Pemetrexed diacid (Formula 2)
Preparation of Pemetrexed diacid (Formula 2) (0081) In a reactor, 1 L of IN NaOH aqueous solution was added, and 143 g of the compound of formula 3 prepared in Example 1 was added thereto at 5-15° C. After stirring at 5-15° C. for 2 hours, the mixture was filtered (HPLC purity: 99.8%). To the filtered solution, 2 L of EtOH was added, and 2N HCl aqueous solution was slowly added thereto dropwise at 5-15° C. to adjust pH to 3.0. The formed crystalline mixture was stirred at 40-50° C. for 1 hour and filtered at 40° C. The filtered product was washed with 2 L of purified water, and further washed with 1 L of EtOH. The filtered product as obtained was added to 4 L of EtOH/purified water (1:1, v/v), and the mixture was stirred at 40-50° C. for 1 hour, and cooled and filtered at room temperature. The filtered product was washed with 2 L of purified water, further washed with 1 L of EtOH, and dried under vacuum at 40-45° C. for 16 hours to obtain 88 g of pemetrexed diacid as white solid (Yield: 95%, HPLC purity: 99.9%, individual impurity content:

References:

SAMYANG BIOPHARMACEUTICALS CORPORATION;KIM, Young Min;KIM, Moon Suk;KIM, Seong Ho;CHO, Jin Suk US2016/214987, 2016, A1 Location in patent:Paragraph 0081

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