4-[2-(2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid

Pale Pink Solid

4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzoic acid (64.6 g 0.19 mol) Add 1L four-necked flask, add 650ml DMF, stir to dissolve, warm to 50 C, add 0.38molN, N-carbonyldiimidazole, and incubate at 60 C for 2 hours, add L-glutamic acid diethyl ester (0.38mol), and warm to Reaction at 80 C for 3 hours, evaporated to dryness under reduced pressure, added 800ml of dichloromethane to dissolve, poured into a mixed solution of 1600ml pure water and 160ml triethylamine, stirred and separated, separated the organic phase, washed twice with pure water 1600ml × 2 Dry, evaporate to dryness, add 500ml of absolute ethanol and stir to dissolve. Add 72g of p-toluenesulfonic acid monohydrate and 200ml of absolute ethanol solution dropwise under reflux. After the addition is complete, reflux for 1 hour, cool down and crystallize, suction filter, and dry. 87.2 g of crude product was obtained (molar yield 70.1%, purity 92.3%, impurity V content was 6.52%).Add 87.2g of the above crude product to a three-necked reaction flask, add 350ml of N, N-dimethylformamide, heat to 40-45 C, stir to dissolve, add 700ml of absolute ethanol dropwise after complete dissolution, and slowly precipitate a solid. The temperature was lowered to room temperature, and the mixture was crystallized by stirring for 1-2 hours. The solid was filtered to obtain 69.8 g, and the yield was 80.0%.The above-mentioned refining operation was repeated once to obtain 55.4 g of a solid (purity: 98.2%, impurity V content: 0.07%).4-[2-(2-Amino-4, 7-dihydro-4-oxo-3H-pyrrolo[2, 3-d]pyrimidin-5-yl)ethyl]benzoic acid(64, 6g 0.19mol) was added to a 1L four-neck bottle.Add 650 ml of DMF and stir to dissolve, and warm to 50 C.Add 0.38 mol of N, N-carbonyldiimidazole, and incubate at 60 C for 2 hours.Add L-glutamic acid diethyl ester (0.38 mol), and raise the temperature to 80 C for 3 hours.Evaporated to dryness under reduced pressure, and dissolved in 800 ml of dichloromethane.Pour into a mixed solution of 1600 ml of pure water and 160 ml of triethylamine, and mix and discard.The organic phase was separated and washed twice with pure water 1600 ml X 2 .Dry and evaporated to dryness, add 500 ml of absolute ethanol and stir to dissolve.72 g of water p-toluenesulfonic acid and 200 ml of absolute ethanol solution were added dropwise under reflux.After the addition, reflux reaction for 1 hour, cooling and crystallization, The mixture was suction filtered and dried to give a crude material (yield: 77.2 g (yield: 70.1%, purity: 92.3%, impurity V content: 6.52%).Add 87.2 g of the above crude product to a three-neck reaction flask.Add 350 ml of N, N-dimethylformamide, Heat to 40-45C to stir and dissolve. After total dissolution, add 700ml of absolute ethanol.The solid was slowly precipitated, cooled to room temperature, and stirred for 1-2 h.The solid obtained by filtration was 69.8 g, and the yield was 80.0%.The above-mentioned refining operation was repeated once to obtain a solid 55.4 g (purity 98.2%, impurity V includedThe amount is 0.07%)Weigh Weigh 4- [2- (2-amino-4, 7-dihydro-4-oxo-3H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzoic acid (60g 0.2mol) Add to a 500ml four-necked flask, add 200ml of acetic acid, heat to 30 C, stir to dissolve, add acetic anhydride (0.24mol) dropwise, heat to 50 C and hold the reaction for 1 hour, evaporate the acetic acid under reduced pressure, add 300ml of pure water and stir, use 5 % Sodium hydroxide solution to adjust the pH to 6, stir and crystallize for 2 hours, reduce the temperature to 0-5 C, suction filter, and dry to obtain the product 4- [2- (2-acetylamino-4, 7-dihydro-4-oxo -3H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzoic acid (molar yield 97.1%, purity 99.5%).Weigh 4. 4-[2-(2-Amino-4, 7-dihydro-4-oxo-3H-pyrrolo[2, 3-d]pyrimidin-5-yl)ethyl]benzoic acid (60 g 0.2 mol) Add to a 500ml four-neck bottle, Add 200ml of DMF and 60.6g of triethylamine to the temperature to 30 C and stir to dissolve.Benzyl chloride (0.2 mol) was added dropwise, Warming up to 50C for 1 hour, Evaporate DMF under reduced pressure, Add 200ml of pure water and stir.Adjust the pH to 5 with dilute hydrochloric acid, stir the crystallization, Cool down to 0-5C suction filtration, Drying the product 4-[2-(2-benzylamino-4, 7-dihydro-4-oxo-3H-pyrrolo[2, 3-d]pyrimidin-5-yl)ethyl]benzoic acid (molar Yield 95.8%, purity 99.0%)4-[2-(2-Amino-4, 7-dihydro-4-oxo-3H-pyrrolo[2, 3-d]pyrimidin-5-yl)ethyl]benzoic acid (64.6 g 0.19 mol)Add 1L four-necked bottle, add 650ml DMF and stir to dissolve.The temperature was raised to 50 C, 0.38 mol of N, carbonyl diimidazole was added, and the reaction was kept at 60 C for 2 hours, and L-glutamic acid diethyl ester (0.38 mol) was added thereto, and the mixture was heated to 80 C for 3 hours, and evaporated to dryness under reduced pressure.After adding 800 ml of dichloromethane to dissolve, pour into a mixed solution of 1600 ml of pure water and 160 ml of triethylamine, and stir to separate the liquid.The organic phase was separated, washed twice with pure water 1600 ml×2, dried and evaporated to dryness, and stirred and dissolved by adding 500 ml of absolute ethanol.72 g of p-toluenesulfonic acid monohydrate and 200 ml of absolute ethanol solution were added dropwise under reflux, and the reaction was refluxed for 1 hour.The crystal was cooled, filtered, and dried to obtain 87.2 g of a crude product (molar yield 70.1%, purity 92.3%, impurity VI content 6.52%). 87.2 g of the above crude product was added to a three-neck reaction flask, and 350 ml of N, N-dimethylformamide was added.Heat to 40-45 C to stir and dissolve. After total dissolution, add 700 ml of absolute ethanol.The solid was gradually precipitated, and the temperature was lowered to room temperature, and the mixture was stirred and crystallized for 1-2 h, and filtered to give a solid, 69.8 g, yield: 80.0%.The above purification operation was repeated once to obtain 55.4 g of a solid (purity: 98.2%, impurity VI content: 0.07%).

Pemetrexed intermediate

Molecular Weight:298.30
XLogP3:1
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:298.10659032
Monoisotopic Mass:298.10659032
Topological Polar Surface Area:121
Heavy Atom Count:22
Complexity:485
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes