Preparation process for synthesizing high-purity Pemedolac
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A preparation process, a technology for pemetrexed acid, applied in the field of medicine
Active Publication Date: 2013-01-23
BEIJING LUNARSUN PHARMA
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[0021] Domestically, there are many literature reports on the preparation of pemetrexed by the above two methods, and the yield of pemetrexed is not high and the purity is not reported. The inventor has carried out small-scale and pilot-scale development of the above two routes according to the literature method, and the yield is also low. The more critical thing is that the purity of the prepared pemetic acid is only about 90%, which is far from meeting the market demand.
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Embodiment 1
[0058] 1. Preparation of 3-(4-methoxycarbonyl)phenyl-1-hydroxypropyl sodium sulfonate (A1)
[0059]
[0060] Under nitrogen protection, 220kg of dimethylformamide, 9.4kg of lithium acetate dihydrate, 10.6kg of lithium chloride, 18kg of methyl p-bromobenzoate, 6.8kg of propenol, and 5.4 kg of tetrabutylammonium bromide were added to a 500L reactor. kg. Raise the temperature to 85-90 degrees, then add 0.38 kg of palladium acetate, continue stirring for about 0.5 h, and monitor by TLC until the reaction is complete. After the reaction is complete, add the feed liquid to 330L water and extract twice with ethyl acetate, 150kg each time, combine the organic phases, wash once with 100kg water, and separate the organic phases; add 40kgNaHSO 3 Aqueous solution (containing NaHSO 3 8kg), stirred and crystallized to collect the solid, and dried at 45°C to obtain 22.4kg of light yellow solid (A1), with a yield of 90% and a purity (partially decomposed into aldehyde when detected by HP...
Embodiment 2
[0082] The following work is the scale-up production record of pemetacid prepared by the present inventors via route 1.
[0083] 1. Preparation of 3-(4-methoxycarbonyl)phenyl-1-propanal (B1)
[0084]
[0085] Under nitrogen protection, 220kg of DMF, 9.4kg of lithium acetate dihydrate, 10.6kg of lithium chloride, 18kg of methyl p-bromobenzoate, 6.8kg of propenol, and 5.4kg of tetrabutylammonium bromide were added to a 200L reactor. Raise the temperature to 85-90 degrees, then add 0.38 kg of palladium acetate, continue stirring for about 0.5 h, and monitor by TLC until the reaction is complete. After the reaction is complete, add the feed liquid to 330L of water, extract twice with ethyl acetate, 150kg each time, combine the organic phase, and wash once with 100kg of water, separate the organic phase; turn on the heating, control the temperature below 45 degrees to evaporate the solvent, 15kg of oil (B1) was obtained with a purity of 56% (22.5% impurity in 22min, MS analysi...
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Abstract
The invention relates to the technical field of medicine, and specifically provides a preparation process for synthesizing high-purity Pemedolac. The invention solves the problem that the original process has very low enlarging yield by preparing a stable and high-purity intermediate sodium 3-(4-methoxycarbonyl)phenyl-1-hdyroxypropylsulphonate, establishes a fundamental base for preparing the high-purity Pemedolac at the same time, and further effectively controls the production of key impurities by using weak alkali salts of Pemedolac in a final purification stage; thus, the yield of the production process is high, and the quality of the product is extremely good; and the method is more convenient to prepare a high-purity anticancer drug pemetrexed disodium. At the same time, the preparation process provided by the invention has mild process conditions; the solvent is convenient to be recycled and applied mechanically; the preparation process provided by the invention is more energy-saving and environment-friendly. The structure of the Pemedolac is shown in the specification.
Description
, technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a synthetic high-purity pemetremic acid (chemical name: 4-[2-(2-amino-4(3H)-4-oxo-7-hydrogen-pyrrolo[2, 3-d] pyrimidin-5 base-) ethyl] benzoic acid) preparation process. [0002] 2. Background technology [0003] Pemetrexed acid is an important intermediate of the new folic acid antineoplastic drug pemetrexed disodium (Alimta, pemetrexates disodium). Pemetrexed disodium is a folic acid antagonist, which mainly acts on DNA base synthetase, and blocks the DNA synthesis of tumor cells by inhibiting a variety of DNA base synthetases (GARFT, DHFR, TS), thereby achieving inhibition and the purpose of eradicating tumor cells. Pemetrexed disodium was developed by Eli Lilly Company of the United States. It was first listed in the United States in 2004 for the treatment of malignant pleural mesothelioma and non-small cell lung cancer. In February 2004, it was approved...
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