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A kind of technology of pemetrexed disodium and dialkoxy, applied in the field of organic medicinal chemistry
Active Publication Date: 2015-12-02
JIANGXI AGRICULTURAL UNIVERSITY
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[0009] The object of the present invention is to provide a kind of preparation method of pemetrexed disodium that preparation cost is cheap, is suitable for industrialized production, and this method solves the problems in the prior art The problems of high preparation cost and difficulty in industrialized production
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Embodiment 1
[0037] Methyl bromomethylbenzoate (228.0g, 1.00mol), triphenylphosphine (288.2g, 1.10mol) and tetrahydrofuran (1.2L) were placed in a three-necked flask and stirred at 25°C for 2h. The reaction solution was cooled to 5°C, potassium tert-butoxide (112 g, 1.00 mol) was added in batches, and stirring was continued at room temperature for 2 h after the addition was complete. Recool the reaction solution to 5°C, add dropwise a mixture of 3,3-dimethoxypropanal (118.0 g, 1.00 mol) and tetrahydrofuran (118 mL), and continue stirring at room temperature for 5 h after the dropwise addition. Recover solvent THF, add ethyl acetate, wash with hot water, dry, recover ethyl acetate to obtain methyl 4-(4,4-dimethoxy-1-butenyl)benzoate (237.5g, 95%) .
Embodiment 2
[0039] Put 1,1-dimethoxy-3-bromopropane (182.0g, 1.00mol), triphenylphosphine (288.2g, 1.10mol) and tetrahydrofuran (0.9L) in a three-necked flask and stir at 25°C 2h. The reaction solution was cooled to 5°C, potassium tert-butoxide (112 g, 1.00 mol) was added in batches, and stirring was continued at room temperature for 2 h after the addition was complete. Recool the reaction solution to 0-5°C, add a mixture of methyl p-aldehyde benzoate (164.0 g, 1.00 mol) and tetrahydrofuran (164 mL) dropwise, and continue stirring at room temperature for 5 h after the dropwise addition. Recover solvent THF, add ethyl acetate, wash with hot water, dry, recover ethyl acetate to obtain methyl 4-(4,4-dimethoxy-1-butenyl)benzoate (240.0g, 96%) .
Embodiment 3
[0041] Place 4-(4,4-dimethoxy-1-butenyl)methyl benzoate (200g, 0.80mol) and 1,2-dichloroethane (1L) in a three-necked flask and cool to 5 ℃, N-bromosuccinimide (155.7 g, 0.88 mol) was added in batches, and stirring was continued at room temperature for 5 h after the addition was complete. Re-cool the reaction solution to 5°C, add dilute hydrochloric acid (1mol / L) dropwise, stir for 0.5h, separate the layers, wash the organic layer with saturated sodium bicarbonate, wash with water, wash with saturated brine, dry, and recover the solvent to obtain 4- Methyl (3-formyl-3-bromo-1-propenyl)benzoate (146.6g, 65%).
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Abstract
The invention discloses a preparation method of pemetrexed disodium, which comprises the following steps: preparing 4-(4,4-dialkoxy-1-butenyl)benzoate 6 and 4-(3-formyl-3-halo-1-propenyl)benzoate 7, carrying out ring-closing reaction on the compound 7 and 2,4-diamido-6-hydroxypyrimidine under the action of an alkali to obtain a compound 9; carrying saponification on the compound 9, and acidifying to obtain a compound 10; carrying out condensation reaction on the compound 10 and diethyl L-glutamate to obtain a compound 11; carrying out catalytic hydrogenation reaction on the compound 11 under the action of a catalyst to obtain a compound 12; and carrying out hydrolysis reaction on the compound 12 under the action of an alkali to obtain the target product pemetrexed disodium 1. The method has the advantages of accessible raw materials, wide sources, low preparation cost and low price, is suitable for industrial production, and solves the problems of high preparation cost and difficulty for industrial production in the prior art.
Description
technical field [0001] The invention relates to the field of organic medicinal chemistry, in particular to a preparation method of pemetrexed disodium. Background technique [0002] Pemetrexed disodium (Pemetrexeddisodium), the chemical name is N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine) -5-yl)ethyl]benzoyl]-L-glutamic acid disodium salt is a multi-targeted antifolate agent developed by Eli Lilly Company of the United States. It was first launched in the United States in 2004. For the treatment of mesothelioma, the trade name is Alimta. This product can play an anti-cancer role by inhibiting a variety of folic acid-dependent enzymes. This product can also inhibit thymidylate synthase (TS), dihydrofolate reductase and glyceramide nucleotide transformylase and other metabolic enzymes, hindering the synthesis of purine and pyrimidine. Its structural formula is shown in formula 1 below: [0003] [0004] Among the pemetrexed disodium synthesis routes r...
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