Raltitrexed impurity C and preparation and application thereof
A technology of raltitrexed and impurities, applied in the field of medicinal chemistry, can solve the problems of high incidence of toxic and side effects in the blood system, and achieve the effect of reducing side effects
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Embodiment 1
[0041] The preparation of embodiment 1 impurity C
[0042] ① Preparation of 5-nitro-2-thiophenoyl chloride
[0043] Put 30g of 5-nitro-2-thiophenecarboxylic acid and 50ml of thionyl chloride into a 100ml three-neck flask, raise the temperature, control the internal temperature to 75°C-80°C and stir for 2 hours, take about 1ml of the reaction solution, add 2ml of anhydrous Methanol derivatization, using 5-nitro-2-thiophenecarboxylic acid as a control, TLC detection (ethyl acetate: n-hexane = 1:1) to the end of the reaction. The reaction solution was transferred to a 250ml single-necked bottle, concentrated to dryness, and then dried under reduced pressure by adding 30ml of toluene to obtain green needle crystals.
[0044] ② Preparation of N-(5-nitro-2-thiophenoyl)-L-glutamic acid diethyl ester
[0045] Put 35.0g of L-diethyl glutamate, 150ml of dichloromethane and 12.5ml of diisopropylethylamine into a 250ml three-neck flask, lower the temperature, and slowly add 50ml of dich...
Embodiment 2
[0052] The preparation of embodiment 2 impurity C
[0053] ① Preparation of 5-nitro-2-thiophenoyl chloride
[0054] Put 30g of 5-nitro-2-thiophenecarboxylic acid and 50ml of phosphorus oxychloride into a 100ml three-neck flask, raise the temperature, control the internal temperature to 75°C-80°C and stir for 2 hours, then take about 1ml of the reaction solution and add 2ml of anhydrous methanol Derivatization, using 5-nitro-2-thiophenecarboxylic acid as a control, TLC detection (ethyl acetate: n-hexane = 1:1) to the end of the reaction. The reaction solution was transferred to a 250ml single-necked bottle, concentrated to dryness, and then dried under reduced pressure by adding 30ml of toluene to obtain green needle crystals.
[0055] ② Preparation of N-(5-nitro-2-thiophenoyl)-L-glutamic acid diethyl ester
[0056] Put 35.0g of L-diethyl glutamate, 150ml of dichloromethane and 12.5ml of ethylenediamine into a 250ml three-neck flask, lower the temperature, and slowly add 50ml...
Embodiment 3
[0063] The preparation of embodiment 3 impurity C
[0064] ① Preparation of 5-nitro-2-thiophenoyl chloride
[0065] Put 30g of 5-nitro-2-thiophenecarboxylic acid and 50ml of phosphorus trichloride into a 100ml three-neck flask, raise the temperature, control the internal temperature to 75°C-80°C and stir for 2 hours, then take about 1ml of the reaction solution and add 2ml of anhydrous methanol Derivatization, using 5-nitro-2-thiophenecarboxylic acid as a control, TLC detection (ethyl acetate: n-hexane = 1:1) to the end of the reaction. The reaction solution was transferred to a 250ml single-necked bottle, concentrated to dryness, and then dried under reduced pressure by adding 30ml of toluene to obtain green needle crystals.
[0066] ② Preparation of N-(5-nitro-2-thiophenoyl)-L-glutamic acid diethyl ester
[0067] Put 35.0g of L-diethyl glutamate, 150ml of dichloromethane and 12.5ml of DBU into a 250ml three-necked bottle, lower the temperature, and slowly add 50ml of dichl...
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